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CHALLENGES WHEN TREATING CUTANEOUS LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Why we need to treat CL
bull Accelerate healing
bull Minimize scarring
bull Prevent complicated forms (RCL DCL MCL)
bull Reduced transmission in ACL
1 Clinical characteristics of the lesion(s) bull Number of lesions bull Type of lesion (ulcers nodules
plaques) bull Lesionrsquos size bull Anatomical localization bull Over infections
2 Parasite characteristics bull Different species and natural
history of the infecting Leishmania parasite
bull Parasite intrinsic variability
3
3 Host Factors bull Age amp Gender bull Concomitant diseases bull Host immune status bull Patientrsquos behaviours and perceptions
4 Other Factors bull Drugs availability bull Cost bull Travellers displaced and refugees populations
Aspects influencing the decision of how treating CL
1 Clinical characteristics of the lesion(s)
bull CL is a diseases with a spectrum clinical manifestations 4
5
Country Specie Subjects Characteristics Reference
Turkey L tropica 7172 95 ge 4 lesions Yemisen M et al 2012
575 lesions in face
305 nodular lesions
Nizip Turkey L tropica 416 61 Female Salman IS et al 2013
57 ge1 lesion
Mainly in face
Sri Lanka L tropica 446 659 Males Sandanayaka R et al 2014
L major 434 nodules
32 crusts
323 in face
Iran L major 849 592 males Rostami N et al 2013
45 ge1 lesion
96 gt4 lesions
Iran L major 6898801 7 children lt13 YO Layegh P et al 2013
77 leskons in face
37 papules
Iran L major 1315 618 men Karami M et al 2013
L tropica 365 nodules
Aleppo L major 1750 80 in lt16 YO Douba MD et al 2012
886 lesions in face
Bam Iran L tropica 9346 59 hands Sharifi I et al 2011
28 face
60 ulcers
Burkina Faso 7444 275 lt15 YO Bamba S et al 2o13
Spain L infantum 149 52 Plaques Aguado M et al 2013
57 ge1 lesion
18 lesions in face
Colombia L panamensis 380 (children) 46 lesions ge 3 cms Blanco VM et al 2013
53 elegibkle for Local Tx
Brazil L braziliensis 470 29 ge1 lesion Pontello Junior R et al 2013
Who are the most affected and the most common type of lesions
2 Leishmania parasite characteristics 6
Self Healing cure rates 7
Specie Time to self cure Country Administration
L major 3 months 21 Saudi Arabia Oral
3 months 53 Iran Oral
2 months 13-63 Iran Topical
25 months 61 Tunisia Oral
L tropica 12 Months 0-10 Iran Oral
L panamensis 1 month 0 Panama Oral
12 months 37 Colombia Oral
L mexicana 3 months 68 Guatemala Topical
L braziliensis 3 months 2 Guatemala Topical
There is sufficient information supporting the intrinsic differences in Leishmania species sensitivity to different antileishmania drugs
Studies using the amastigote-macrophage model Sensitivity of promastigotes and amastigotes in vitro assays Murine macrophage ndashamastigote model
Sodium Stibogluconate L braziliensis and L donovani more sensitive than L mexicana L amazonensis and L guyanensis
Amphothericin B L mexicana is less sensitive than L donovani
Miltefosine L donovani more sensitive than L braziliensis L guyanensis and L mexicana
Paromomycin L major and L tropica more sensitive than L braziliensis and L mexicana
Azoles Contradictory information
Leishmania intrinsic variation
Drug Country Leishmania specie Cure rate Reference
SbV
Brazil (Rio Janeiro) L braziliensis 84 Oliveira-Neto 1993
Brazil (Bahia) L braziliensis 51 Romero 2001
Guatemala L braziliensis 90 Arana 1994
Peruacute L braziliensis 70 Areacutevalo 2007
Colombia L braziliensis L panamensis
67 93 81
Palacios 2001 Velez 1997 Soto 2005
Ecuador L panamensis (+++) L guyanensis (+)
91 Guderian 1991
Brazil L guyanensis 26 Romero 2001
Peruacute L guyanensis 92 Areacutevalo 2007
Clinical response to treatment
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Why we need to treat CL
bull Accelerate healing
bull Minimize scarring
bull Prevent complicated forms (RCL DCL MCL)
bull Reduced transmission in ACL
1 Clinical characteristics of the lesion(s) bull Number of lesions bull Type of lesion (ulcers nodules
plaques) bull Lesionrsquos size bull Anatomical localization bull Over infections
2 Parasite characteristics bull Different species and natural
history of the infecting Leishmania parasite
bull Parasite intrinsic variability
3
3 Host Factors bull Age amp Gender bull Concomitant diseases bull Host immune status bull Patientrsquos behaviours and perceptions
4 Other Factors bull Drugs availability bull Cost bull Travellers displaced and refugees populations
Aspects influencing the decision of how treating CL
1 Clinical characteristics of the lesion(s)
bull CL is a diseases with a spectrum clinical manifestations 4
5
Country Specie Subjects Characteristics Reference
Turkey L tropica 7172 95 ge 4 lesions Yemisen M et al 2012
575 lesions in face
305 nodular lesions
Nizip Turkey L tropica 416 61 Female Salman IS et al 2013
57 ge1 lesion
Mainly in face
Sri Lanka L tropica 446 659 Males Sandanayaka R et al 2014
L major 434 nodules
32 crusts
323 in face
Iran L major 849 592 males Rostami N et al 2013
45 ge1 lesion
96 gt4 lesions
Iran L major 6898801 7 children lt13 YO Layegh P et al 2013
77 leskons in face
37 papules
Iran L major 1315 618 men Karami M et al 2013
L tropica 365 nodules
Aleppo L major 1750 80 in lt16 YO Douba MD et al 2012
886 lesions in face
Bam Iran L tropica 9346 59 hands Sharifi I et al 2011
28 face
60 ulcers
Burkina Faso 7444 275 lt15 YO Bamba S et al 2o13
Spain L infantum 149 52 Plaques Aguado M et al 2013
57 ge1 lesion
18 lesions in face
Colombia L panamensis 380 (children) 46 lesions ge 3 cms Blanco VM et al 2013
53 elegibkle for Local Tx
Brazil L braziliensis 470 29 ge1 lesion Pontello Junior R et al 2013
Who are the most affected and the most common type of lesions
2 Leishmania parasite characteristics 6
Self Healing cure rates 7
Specie Time to self cure Country Administration
L major 3 months 21 Saudi Arabia Oral
3 months 53 Iran Oral
2 months 13-63 Iran Topical
25 months 61 Tunisia Oral
L tropica 12 Months 0-10 Iran Oral
L panamensis 1 month 0 Panama Oral
12 months 37 Colombia Oral
L mexicana 3 months 68 Guatemala Topical
L braziliensis 3 months 2 Guatemala Topical
There is sufficient information supporting the intrinsic differences in Leishmania species sensitivity to different antileishmania drugs
Studies using the amastigote-macrophage model Sensitivity of promastigotes and amastigotes in vitro assays Murine macrophage ndashamastigote model
Sodium Stibogluconate L braziliensis and L donovani more sensitive than L mexicana L amazonensis and L guyanensis
Amphothericin B L mexicana is less sensitive than L donovani
Miltefosine L donovani more sensitive than L braziliensis L guyanensis and L mexicana
Paromomycin L major and L tropica more sensitive than L braziliensis and L mexicana
Azoles Contradictory information
Leishmania intrinsic variation
Drug Country Leishmania specie Cure rate Reference
SbV
Brazil (Rio Janeiro) L braziliensis 84 Oliveira-Neto 1993
Brazil (Bahia) L braziliensis 51 Romero 2001
Guatemala L braziliensis 90 Arana 1994
Peruacute L braziliensis 70 Areacutevalo 2007
Colombia L braziliensis L panamensis
67 93 81
Palacios 2001 Velez 1997 Soto 2005
Ecuador L panamensis (+++) L guyanensis (+)
91 Guderian 1991
Brazil L guyanensis 26 Romero 2001
Peruacute L guyanensis 92 Areacutevalo 2007
Clinical response to treatment
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
1 Clinical characteristics of the lesion(s) bull Number of lesions bull Type of lesion (ulcers nodules
plaques) bull Lesionrsquos size bull Anatomical localization bull Over infections
2 Parasite characteristics bull Different species and natural
history of the infecting Leishmania parasite
bull Parasite intrinsic variability
3
3 Host Factors bull Age amp Gender bull Concomitant diseases bull Host immune status bull Patientrsquos behaviours and perceptions
4 Other Factors bull Drugs availability bull Cost bull Travellers displaced and refugees populations
Aspects influencing the decision of how treating CL
1 Clinical characteristics of the lesion(s)
bull CL is a diseases with a spectrum clinical manifestations 4
5
Country Specie Subjects Characteristics Reference
Turkey L tropica 7172 95 ge 4 lesions Yemisen M et al 2012
575 lesions in face
305 nodular lesions
Nizip Turkey L tropica 416 61 Female Salman IS et al 2013
57 ge1 lesion
Mainly in face
Sri Lanka L tropica 446 659 Males Sandanayaka R et al 2014
L major 434 nodules
32 crusts
323 in face
Iran L major 849 592 males Rostami N et al 2013
45 ge1 lesion
96 gt4 lesions
Iran L major 6898801 7 children lt13 YO Layegh P et al 2013
77 leskons in face
37 papules
Iran L major 1315 618 men Karami M et al 2013
L tropica 365 nodules
Aleppo L major 1750 80 in lt16 YO Douba MD et al 2012
886 lesions in face
Bam Iran L tropica 9346 59 hands Sharifi I et al 2011
28 face
60 ulcers
Burkina Faso 7444 275 lt15 YO Bamba S et al 2o13
Spain L infantum 149 52 Plaques Aguado M et al 2013
57 ge1 lesion
18 lesions in face
Colombia L panamensis 380 (children) 46 lesions ge 3 cms Blanco VM et al 2013
53 elegibkle for Local Tx
Brazil L braziliensis 470 29 ge1 lesion Pontello Junior R et al 2013
Who are the most affected and the most common type of lesions
2 Leishmania parasite characteristics 6
Self Healing cure rates 7
Specie Time to self cure Country Administration
L major 3 months 21 Saudi Arabia Oral
3 months 53 Iran Oral
2 months 13-63 Iran Topical
25 months 61 Tunisia Oral
L tropica 12 Months 0-10 Iran Oral
L panamensis 1 month 0 Panama Oral
12 months 37 Colombia Oral
L mexicana 3 months 68 Guatemala Topical
L braziliensis 3 months 2 Guatemala Topical
There is sufficient information supporting the intrinsic differences in Leishmania species sensitivity to different antileishmania drugs
Studies using the amastigote-macrophage model Sensitivity of promastigotes and amastigotes in vitro assays Murine macrophage ndashamastigote model
Sodium Stibogluconate L braziliensis and L donovani more sensitive than L mexicana L amazonensis and L guyanensis
Amphothericin B L mexicana is less sensitive than L donovani
Miltefosine L donovani more sensitive than L braziliensis L guyanensis and L mexicana
Paromomycin L major and L tropica more sensitive than L braziliensis and L mexicana
Azoles Contradictory information
Leishmania intrinsic variation
Drug Country Leishmania specie Cure rate Reference
SbV
Brazil (Rio Janeiro) L braziliensis 84 Oliveira-Neto 1993
Brazil (Bahia) L braziliensis 51 Romero 2001
Guatemala L braziliensis 90 Arana 1994
Peruacute L braziliensis 70 Areacutevalo 2007
Colombia L braziliensis L panamensis
67 93 81
Palacios 2001 Velez 1997 Soto 2005
Ecuador L panamensis (+++) L guyanensis (+)
91 Guderian 1991
Brazil L guyanensis 26 Romero 2001
Peruacute L guyanensis 92 Areacutevalo 2007
Clinical response to treatment
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
1 Clinical characteristics of the lesion(s)
bull CL is a diseases with a spectrum clinical manifestations 4
5
Country Specie Subjects Characteristics Reference
Turkey L tropica 7172 95 ge 4 lesions Yemisen M et al 2012
575 lesions in face
305 nodular lesions
Nizip Turkey L tropica 416 61 Female Salman IS et al 2013
57 ge1 lesion
Mainly in face
Sri Lanka L tropica 446 659 Males Sandanayaka R et al 2014
L major 434 nodules
32 crusts
323 in face
Iran L major 849 592 males Rostami N et al 2013
45 ge1 lesion
96 gt4 lesions
Iran L major 6898801 7 children lt13 YO Layegh P et al 2013
77 leskons in face
37 papules
Iran L major 1315 618 men Karami M et al 2013
L tropica 365 nodules
Aleppo L major 1750 80 in lt16 YO Douba MD et al 2012
886 lesions in face
Bam Iran L tropica 9346 59 hands Sharifi I et al 2011
28 face
60 ulcers
Burkina Faso 7444 275 lt15 YO Bamba S et al 2o13
Spain L infantum 149 52 Plaques Aguado M et al 2013
57 ge1 lesion
18 lesions in face
Colombia L panamensis 380 (children) 46 lesions ge 3 cms Blanco VM et al 2013
53 elegibkle for Local Tx
Brazil L braziliensis 470 29 ge1 lesion Pontello Junior R et al 2013
Who are the most affected and the most common type of lesions
2 Leishmania parasite characteristics 6
Self Healing cure rates 7
Specie Time to self cure Country Administration
L major 3 months 21 Saudi Arabia Oral
3 months 53 Iran Oral
2 months 13-63 Iran Topical
25 months 61 Tunisia Oral
L tropica 12 Months 0-10 Iran Oral
L panamensis 1 month 0 Panama Oral
12 months 37 Colombia Oral
L mexicana 3 months 68 Guatemala Topical
L braziliensis 3 months 2 Guatemala Topical
There is sufficient information supporting the intrinsic differences in Leishmania species sensitivity to different antileishmania drugs
Studies using the amastigote-macrophage model Sensitivity of promastigotes and amastigotes in vitro assays Murine macrophage ndashamastigote model
Sodium Stibogluconate L braziliensis and L donovani more sensitive than L mexicana L amazonensis and L guyanensis
Amphothericin B L mexicana is less sensitive than L donovani
Miltefosine L donovani more sensitive than L braziliensis L guyanensis and L mexicana
Paromomycin L major and L tropica more sensitive than L braziliensis and L mexicana
Azoles Contradictory information
Leishmania intrinsic variation
Drug Country Leishmania specie Cure rate Reference
SbV
Brazil (Rio Janeiro) L braziliensis 84 Oliveira-Neto 1993
Brazil (Bahia) L braziliensis 51 Romero 2001
Guatemala L braziliensis 90 Arana 1994
Peruacute L braziliensis 70 Areacutevalo 2007
Colombia L braziliensis L panamensis
67 93 81
Palacios 2001 Velez 1997 Soto 2005
Ecuador L panamensis (+++) L guyanensis (+)
91 Guderian 1991
Brazil L guyanensis 26 Romero 2001
Peruacute L guyanensis 92 Areacutevalo 2007
Clinical response to treatment
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
5
Country Specie Subjects Characteristics Reference
Turkey L tropica 7172 95 ge 4 lesions Yemisen M et al 2012
575 lesions in face
305 nodular lesions
Nizip Turkey L tropica 416 61 Female Salman IS et al 2013
57 ge1 lesion
Mainly in face
Sri Lanka L tropica 446 659 Males Sandanayaka R et al 2014
L major 434 nodules
32 crusts
323 in face
Iran L major 849 592 males Rostami N et al 2013
45 ge1 lesion
96 gt4 lesions
Iran L major 6898801 7 children lt13 YO Layegh P et al 2013
77 leskons in face
37 papules
Iran L major 1315 618 men Karami M et al 2013
L tropica 365 nodules
Aleppo L major 1750 80 in lt16 YO Douba MD et al 2012
886 lesions in face
Bam Iran L tropica 9346 59 hands Sharifi I et al 2011
28 face
60 ulcers
Burkina Faso 7444 275 lt15 YO Bamba S et al 2o13
Spain L infantum 149 52 Plaques Aguado M et al 2013
57 ge1 lesion
18 lesions in face
Colombia L panamensis 380 (children) 46 lesions ge 3 cms Blanco VM et al 2013
53 elegibkle for Local Tx
Brazil L braziliensis 470 29 ge1 lesion Pontello Junior R et al 2013
Who are the most affected and the most common type of lesions
2 Leishmania parasite characteristics 6
Self Healing cure rates 7
Specie Time to self cure Country Administration
L major 3 months 21 Saudi Arabia Oral
3 months 53 Iran Oral
2 months 13-63 Iran Topical
25 months 61 Tunisia Oral
L tropica 12 Months 0-10 Iran Oral
L panamensis 1 month 0 Panama Oral
12 months 37 Colombia Oral
L mexicana 3 months 68 Guatemala Topical
L braziliensis 3 months 2 Guatemala Topical
There is sufficient information supporting the intrinsic differences in Leishmania species sensitivity to different antileishmania drugs
Studies using the amastigote-macrophage model Sensitivity of promastigotes and amastigotes in vitro assays Murine macrophage ndashamastigote model
Sodium Stibogluconate L braziliensis and L donovani more sensitive than L mexicana L amazonensis and L guyanensis
Amphothericin B L mexicana is less sensitive than L donovani
Miltefosine L donovani more sensitive than L braziliensis L guyanensis and L mexicana
Paromomycin L major and L tropica more sensitive than L braziliensis and L mexicana
Azoles Contradictory information
Leishmania intrinsic variation
Drug Country Leishmania specie Cure rate Reference
SbV
Brazil (Rio Janeiro) L braziliensis 84 Oliveira-Neto 1993
Brazil (Bahia) L braziliensis 51 Romero 2001
Guatemala L braziliensis 90 Arana 1994
Peruacute L braziliensis 70 Areacutevalo 2007
Colombia L braziliensis L panamensis
67 93 81
Palacios 2001 Velez 1997 Soto 2005
Ecuador L panamensis (+++) L guyanensis (+)
91 Guderian 1991
Brazil L guyanensis 26 Romero 2001
Peruacute L guyanensis 92 Areacutevalo 2007
Clinical response to treatment
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
2 Leishmania parasite characteristics 6
Self Healing cure rates 7
Specie Time to self cure Country Administration
L major 3 months 21 Saudi Arabia Oral
3 months 53 Iran Oral
2 months 13-63 Iran Topical
25 months 61 Tunisia Oral
L tropica 12 Months 0-10 Iran Oral
L panamensis 1 month 0 Panama Oral
12 months 37 Colombia Oral
L mexicana 3 months 68 Guatemala Topical
L braziliensis 3 months 2 Guatemala Topical
There is sufficient information supporting the intrinsic differences in Leishmania species sensitivity to different antileishmania drugs
Studies using the amastigote-macrophage model Sensitivity of promastigotes and amastigotes in vitro assays Murine macrophage ndashamastigote model
Sodium Stibogluconate L braziliensis and L donovani more sensitive than L mexicana L amazonensis and L guyanensis
Amphothericin B L mexicana is less sensitive than L donovani
Miltefosine L donovani more sensitive than L braziliensis L guyanensis and L mexicana
Paromomycin L major and L tropica more sensitive than L braziliensis and L mexicana
Azoles Contradictory information
Leishmania intrinsic variation
Drug Country Leishmania specie Cure rate Reference
SbV
Brazil (Rio Janeiro) L braziliensis 84 Oliveira-Neto 1993
Brazil (Bahia) L braziliensis 51 Romero 2001
Guatemala L braziliensis 90 Arana 1994
Peruacute L braziliensis 70 Areacutevalo 2007
Colombia L braziliensis L panamensis
67 93 81
Palacios 2001 Velez 1997 Soto 2005
Ecuador L panamensis (+++) L guyanensis (+)
91 Guderian 1991
Brazil L guyanensis 26 Romero 2001
Peruacute L guyanensis 92 Areacutevalo 2007
Clinical response to treatment
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Self Healing cure rates 7
Specie Time to self cure Country Administration
L major 3 months 21 Saudi Arabia Oral
3 months 53 Iran Oral
2 months 13-63 Iran Topical
25 months 61 Tunisia Oral
L tropica 12 Months 0-10 Iran Oral
L panamensis 1 month 0 Panama Oral
12 months 37 Colombia Oral
L mexicana 3 months 68 Guatemala Topical
L braziliensis 3 months 2 Guatemala Topical
There is sufficient information supporting the intrinsic differences in Leishmania species sensitivity to different antileishmania drugs
Studies using the amastigote-macrophage model Sensitivity of promastigotes and amastigotes in vitro assays Murine macrophage ndashamastigote model
Sodium Stibogluconate L braziliensis and L donovani more sensitive than L mexicana L amazonensis and L guyanensis
Amphothericin B L mexicana is less sensitive than L donovani
Miltefosine L donovani more sensitive than L braziliensis L guyanensis and L mexicana
Paromomycin L major and L tropica more sensitive than L braziliensis and L mexicana
Azoles Contradictory information
Leishmania intrinsic variation
Drug Country Leishmania specie Cure rate Reference
SbV
Brazil (Rio Janeiro) L braziliensis 84 Oliveira-Neto 1993
Brazil (Bahia) L braziliensis 51 Romero 2001
Guatemala L braziliensis 90 Arana 1994
Peruacute L braziliensis 70 Areacutevalo 2007
Colombia L braziliensis L panamensis
67 93 81
Palacios 2001 Velez 1997 Soto 2005
Ecuador L panamensis (+++) L guyanensis (+)
91 Guderian 1991
Brazil L guyanensis 26 Romero 2001
Peruacute L guyanensis 92 Areacutevalo 2007
Clinical response to treatment
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
There is sufficient information supporting the intrinsic differences in Leishmania species sensitivity to different antileishmania drugs
Studies using the amastigote-macrophage model Sensitivity of promastigotes and amastigotes in vitro assays Murine macrophage ndashamastigote model
Sodium Stibogluconate L braziliensis and L donovani more sensitive than L mexicana L amazonensis and L guyanensis
Amphothericin B L mexicana is less sensitive than L donovani
Miltefosine L donovani more sensitive than L braziliensis L guyanensis and L mexicana
Paromomycin L major and L tropica more sensitive than L braziliensis and L mexicana
Azoles Contradictory information
Leishmania intrinsic variation
Drug Country Leishmania specie Cure rate Reference
SbV
Brazil (Rio Janeiro) L braziliensis 84 Oliveira-Neto 1993
Brazil (Bahia) L braziliensis 51 Romero 2001
Guatemala L braziliensis 90 Arana 1994
Peruacute L braziliensis 70 Areacutevalo 2007
Colombia L braziliensis L panamensis
67 93 81
Palacios 2001 Velez 1997 Soto 2005
Ecuador L panamensis (+++) L guyanensis (+)
91 Guderian 1991
Brazil L guyanensis 26 Romero 2001
Peruacute L guyanensis 92 Areacutevalo 2007
Clinical response to treatment
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Drug Country Leishmania specie Cure rate Reference
SbV
Brazil (Rio Janeiro) L braziliensis 84 Oliveira-Neto 1993
Brazil (Bahia) L braziliensis 51 Romero 2001
Guatemala L braziliensis 90 Arana 1994
Peruacute L braziliensis 70 Areacutevalo 2007
Colombia L braziliensis L panamensis
67 93 81
Palacios 2001 Velez 1997 Soto 2005
Ecuador L panamensis (+++) L guyanensis (+)
91 Guderian 1991
Brazil L guyanensis 26 Romero 2001
Peruacute L guyanensis 92 Areacutevalo 2007
Clinical response to treatment
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
3 Host factors
Age amp Gender - Children lt5 YO and patients gt70 YO - Child bearing age pregnant and breastfeeding women Concomitant Diseases - Cardiac or renal problems - Gastrointestinal disorders - Immune compromised patients Patientrsquos behaviours and perceptions - Previous use of home made remedies - Treatment preferences outcomes - Perceived diseases seriousness
10
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
4 Other factors
Drugs availability amp Cost
11
WHO Technical Report Series 949 2010
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Leishmaniasis in Travelers
bull CL is one of the top 10 skin diseases among tourists returning from endemic countries with skin problems
bull 16 billion international travel movements will occur up to 2020
bull gt50 travelers are for leisure
bull International travelers are often unaware of the risk of leishmaniasis and appropriate protective measures
(Pavli A amp Meltezou H 2010)
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Adapted from Pavli A amp Meltezou H 2010
Published cases of travel-acquired leishmaniasis
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
14
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Summary
Treatment of CL cases should be based on the following criteria
bull Individual Risk- Benefit ratio
bull Size of lesion -Large lesions (4 or more cm diameter)
bull Site of lesion ndash Lesions on the face joints (ankle wrist or finger)
bull Multiple lesions (more than 4 lesions)
bull Lymphatic spread or dissemination
bull Immune status of patient
bull Availability of the drug or treatment option
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Thank you
16
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
17
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
INNATE IMMUNE MODULATORS IN THE THERAPY OF CUTANEOUS LEISHMANIASIS
AND POST KALA-AZAR LEISHMANIASIS
Byron Arana Head of CL Program DNDi
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Leishmaniasis is an Immunological Disease
Injection of the same parasite (L major) different diseases Balbc (sensitive) generalized disease death C57BL6 (Resistant) small cutaneous self-healing lesion Balbc A strong Th-2 response High IL-10 High antibody Low IF-γ High parasite load visceral disease No cellular reaction (LST) Immuno-suppression (X-ray Thymectomy etc) Resistant Drug treatment reduces parasite load but does not cure Similar to HIV- leishmaniasis co-infection C57BL6 Self cure- lesion Immune to re-infection No sterile immunity Immunosuppression Susceptible just like Balbc HIV-Leish Low IL-10 Low antibody High IF-γ Low parasite
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Post Kala-Azar Leishmaniasis (PKDL)
There is no animal model for PKDL Those who develop PKDL are immune to VL Some have CMI others donrsquot Causes of PKDL Genetics Cytokine interplay parasite load skin immune response suppression by sun light hellip Repeated exposure in high prevalence foci India vs Sudan Those with CMI tend to heal spontaneously or respond better to treatment others very hard to treat
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Immune
System
Anatomical barriers
inflammation phagocytes
macrophages DC NK cells
Pattern recognition
receptors (PRR)
B cell T cell
Innate
(Non-specific)
1st line of defence
Adaptive
(Specific)
2nd line of defence
TLR9
Th2 cells IL4 5 9 13 17E 25
Th1 cells IFN-γ TNFα and β IL-2
Healing
Non-Healing
Up-regulation of Th1 response
Human immune system and leishmaniasis
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Immunotherapy of CL Venezuela
Convit J et al (first article) Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis Lancet 1987 Feb 211(8530)401-5 (many more) Heat-killed Leishmania promastigotes mixed just prior to id injection with live BCG for treating Localized CL 94 patients Randomized 2 groups followed for 214 days Immunotherapy (3 injections) final cure ratehelliphelliphelliphellip 94 Chemotherapy (3 courses of 20 day Sb+5 ) final cure hellip94 Side effects Immunotherapy = 58 Chemotherapy = 524 and some serious Immunotherapy = Low cost safer amp probably similar efficacy to Sb+5
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
In a second randomized double-blind study (Convit J et al J Infect Dis 1989 Jul160(1)104-15)
217 patients in 3 Groups Cure rate
1) Immunotherapy alone (3-4 doses in 4-6 wks) 90
2) Sb+5 (20 daily injections) 95
3) BCG alone control (3-4 doses) 43
Group 2 (Sb+5) shorter time to cure (at wk 20 weeks)
Over 23000 cases treated (11532 between 1990-1999)
Rodriacuteguez N et al Journal of Clinical Microbiology Sept (1994) 2246-225
Jorquera A et al Mem Inst Oswaldo Cruz 200510045-8
Bonfante-Garrido R et al Trans R Soc Trop Med Hyg 1992 86141-8
De Lima H Rodriacuteguez N Trans R Soc Trop Med Hyg 2009103721-6
Immunotherapy of CL Venezuela
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Immunochemotherapy of CL (L braziliensis) to reduce drug dose
24
102 patients in two groups
1 Four series of vaccine + frac12 dose of SSG x 10 days (10 days intervals)
Cure rate = 100 (4747)
2 frac12 dose of SSG x 10 days
Cure rate= 82 (449)
CONCLUSIONS The combination of a single-strain of L amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL
Machado-Pinto J et al Int J Dermatol 2002 41 73-8
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
PKDL immuno-chemotherapy in Sudan
Group-1 Sb+5 (20 mgkgd x40) + Vaccine weekly (x4) Group-2 Sb+5 (20 mgkgd x40) + Placebo weekly (x4) Results Group 1 Group 2 Chemo+ Vaccine Chemo Day 60 87 (1315) 53 (815) Day 90 100 (1515) 40 (615) p lt0004 Vaccine = Leishmania major (AlumALM) vaccine+Bacille Calmette-Gueacuterin (BCG) Musa Am et al 2008 Trans R Soc Trop Med Hyg 10258-63
Proof of Principle Double Blind Randomized Controlled
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Summary
bull Leishmaniasis is a diseases where a proper immune response of the host is necessary to achieve cure
bull Immunotheraphy in combination with chemotherapy have the potential to be a valuable safe and efficacious treatment for PKDL and CL
bull The level of understanding and knowledge of the diseases and of the current available immunomodulators strongly supports its continued development up to the next stage gate
26
Thank you
27
Thank you
27