william blouin, msn, arnp, cpnp miami children’s hospital ingid prague 1 november 2014
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The Future of ImmunologyNew Therapy Options
William Blouin, MSN, ARNP, CPNPMiami Children’s Hospital
INGIDPrague
1 November 2014
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No disclosures relevant to this presentation.
Disclosure
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Provide an overview of new developments and future directions in immunologic therapy for Primary Immune Deficiencies.
Goal
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The Future of Immunology New Therapy Options
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IgG Replacement Therapy Transplantation
◦ Thymus Transplantation◦ Hematapoietic Stem Cell Transplantation & Gene Therapy
The Future of ImmunologyNew Therapy Options
Outline
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IgG Replacement Therapy
1890 - 1910 Animal Sera 1910 - 1930 Human Sera 1940 Cold Ethanol Fractionation 1950 First PID treated 1952 SC IM 1960 Pepsin Treated Late 60’s IVIG 1970 Other Chemical Methods 1980 IVIG Standard Therapy 1990’s SCIG Europe 2000 US SCIG Research 2006 First US SCIG Product 2010 - 2014 New Products IVIG & SCIG 2014 – Future ?
Immunoglobulin Therapy Timeline
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IgG TherapyDoes One Size Fit All?
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Dosing Flexibility
Immunoglobulin Therapy
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• Therapeutic IgG levels varies from patient to patient• Dosing should be individualized • Steady state IgG serum levels provide therapeutic
advantage
• Dosing regimens can be adjusted for optimal outcomes and mitigate wear-off• IVIG: weekly, q 3-4 weeks • SCIG: Frequent, weekly, biweekly• SCIG: Monthly with second compound hyaluronidase
IgG Therapy
1. Bonagura VR et al. J Allergy Clin Immunol 2008;122(1):210-2122. Lucas M et al. J Allergy Clin Immunol 2010;125:1354-1360
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Venous access required◦ Requires a healthcare provider to administer
Large volumes administered (every 3-4 weeks) Premedications commonly needed prior to IVIg administration Higher reports of systemic reactions: chills, fever, headache Less frequent dosing Peaks and troughs
IVIg Therapy
Berger M. Clin Immunol. 2004;112:1-7.
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SCIgWeekly, Biweekly, Monthly
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Venous access not required Gradual absorption (24-72 hours after the infusion) Consistent, steady IgG serum levels maintained with weekly and
biweekly infusions Small volumes administered frequently Pre-medications not required Facilitates self-infusion in home setting, allowing patients to
actively participate in therapy with provider oversight
SCIG Weekly or Biweekly Administration
Berger M. Clin Immunol. 2004;112:1-7.
SCIg Weekly/Biweekly dosing vs. IVIg Monthly
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• Dose should be individualized based on the patient’s clinical response to IgG therapy and serum IgG levels
1. Adapted with permission from Berger M. Clin Immunol 2004;112:1-7
Pharmacokinetic Serum Profile of IVIg and Weekly SCIg
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• Needle length can affect site reactions:− Too short results in increased irritation or leaking− Too long can result in discomfort/pain− Length range: 4 mm, 6 mm, 9 mm, 12 mm, 14 mm
• Gauge/brand can affect flow rate and impact local tolerability− 24, 26, or 27 gauge
• Flexible cannula can kink with excess subcutaneous tissue or movement
• Dry insertion technique is recommended• Rate of infusion may be slower in
pediatric patients, thinner patients and those with renal impairment/CV risk factors
Important Considerations
Younger ME, Aro L, Blouin W, et al. Nursing Guidelines for Administration of Immunoglobulin Replacement Therapy.
Journal of Infusion Nursing. 2013;36(1):58-68.
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◦ Venous access not required◦ Pharmacokinetic serum profile similar to IVIg (peaks and troughs)◦ Given once every 3-4 weeks after initial ramp-up schedule
(seven weeks)
◦ Large volume administered at infusion site(s), 300-600 mLs◦ 2-drug combination administered
Hyaluronidase first, 10% IgG after IgG gets into blood within 5 days
◦ Premedications not required◦ Not indicated for children
SCIg Monthly Administration
1. Wasserman RL et al. JACI. 2012.2. HyQvia Prescribing Information, 2014
SCIg Monthly Dosing vs IVIg Monthly
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Dose should be individualized based on the patient’s clinical response to IgG therapy and serum IgG levels
Serum IgG concentration for IGHy compared with IGIV and IGSC. Representative pharmacokineticcurves for one subject comparing a 4-week infusion of IGIV, a weekly infusion of IGSC, 10% at 143% of the IVdose with the same data points extended across the 4-week period to facilitate comparison with the othercurves, and a 4-week infusion of IGHy at 104% of the IV dose.
Study Day 0 7 14 21 28
1. Wasserman RL et al. JACI. 2012.2. HyQvia Prescribing Information, 2014 17
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Feature SCIg IVIg SCIg MonthlyPharmacokinetics Stable serum trough IgG
levelVariability in serum IgG level between peak and trough
Pharmacokineticallyequivalent to IGIV
Efficacy Clinical efficacy demonstrated in PIDD (noninferior when compared with IVIg)
Clinical efficacy demonstrated in PIDD and other autoimmune disorders
Clinical efficacy demonstrated in PIDD (noninferior when compared with IVIg)
Systemic side effects
Infrequent Frequent More frequent than SCIg
Local site reactions Common Infrequent Common
Administration Self-administration; patient autonomy
Infusion center/ home setting with nursing support for venous access
Predominantly self administration; 7 week ramp up for initiation
Average length of infusion
1 to 2 hours 2 to 4 hours 2-3 hours
Dosing interval Weekly or every 2 weeks Variable – every 2 to 4 weeks Variable- every 3-4 weeks
Warnings Ig Class Ig Class • Ig Class• EU Risk Management Plan • US warnings:
• Antibodies to PH20• Infusion into or
around an infected area can spread a localized infection
Features of Ig Therapies
1. Berger M. Immunol Allergy Clin North Am. 2008;28:413-437.2. Wasserman et al. Journal Allergy Clin Immunol20123.. Bonilla FA, et al. Ann Allergy Asthma Immunol, 2005;94(5)(Suppl1):S1-S634.. Skoda-Smith S, Torgerson TR, Ochs HD. Ther Clin Risk Manag. 2010;6:1-10.5. HyQvia US Prescribing Information, Sept 2014
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Thymus Transplantation
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Complete DiGeorge Anomaly
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Thymus hypoplasia or aplasia
Congenital heart defects
Hypoparathyoidism
DiGeorge Anomaly
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Complete (Athymic) DiGeorge Anomaly
Fatal condition ~1% of all DiGeorge anomaly Diagnosis of athymia is based on blood test
◦ Usually < 50/mm3 T cells (normal 2500 – 5500/mm3)◦ Always < 50/mm3 naïve (CD45RA+CD62L+) T cells ◦Normal naïve number 1580 – 4900/mm3
Diagnosis based on athymia plus one of the following: ◦ Congenital heart disease◦ Hypoparathyroidism◦ CHARGE syndrome◦ 22q11.2 deletion syndrome
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Thymus Transplantation Methods
Harvest & Slice Postnatal Unmatched Thymus
Culture 2 – 3 weeks
Transplant into quadriceps
Biopsy graft at 2 – 3 months
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69 infants with complete DiGeorge 50 of 69 (73%) are alive (median survival rate 8.4
years) 49 of 51 (96%) who survived 1 year have naïve T-
Cells
Thymus Transplantation 2014
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Hematopoietic Stem Cell Transplant & Gene Therapy
Transplant of normal HSC from an allogeneic donor
PIDD Indications• SCID• HIGM• WAS
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Improved diagnosis◦ Newborn screening for SCIDs◦ Best outcomes reported in infants treated with HSCT before 3.5
months Novel therapy approaches
◦ SCID Optimal HSCT pre transplant conditioning Limit toxicity and long term adverse effects Anti-infective measures
◦ Non SCID HSCT – Other PIDs WAS HIGM CGD
HSCT Ongoing Research and Initiatives
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Research goals for the near future include• Identify optimal treatment using HSCT for newborns with SCID• Enroll as many children as possible diagnosed with SCID as
newborns into studies • Characterize all children with low T-cell receptor excision circle
numbers at birth • Determine which children with CGD should receive a transplant • Determine whether full donor chimerism is essential to prevent
post transplantation (e.g. autoimmunity in patients with WAS) • Develop joint studies• Initiate retrospective, prospective, and cross-sectional studies of
other rare non-SCID PIDs• Answer questions raised by the research studies in SCID
HSCT Goals for the Future
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Hematopoietic Stem Cell Transplant & Gene Therapy
Autologous transplant ofgene corrected HSC GENE THERAPY
“personalized therapy”
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Gene therapy conceptualized in 1972. The first FDA-approved gene therapy experiment
in the United States was 1990 for ADA-SCID.
By 2014, approximately 2,000 clinical trials
Gene Therapy
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Gene therapy is the use of DNA to treat disease by delivering therapeutic DNA into a patient's cells. • DNA can replace a mutated or dysfunctional gene with
one that encodes a functional, therapeutic one directly correcting a mutation.
Gene Therapy
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• DNA that encodes a therapeutic protein drug (rather than a natural gene) to provide treatment. DNA is packaged within a vector to get the DNA inside cells. DNA expressed by the cell produces the therapeutic protein
and treats the disease.
Gene Therapy
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Gene Therapy
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Gene Therapy for Primary Immunodeficiencies
In the clinic:SCIDX1 (retro+ SIN retro), ADA (retro +lenti), CGD (retro + lenti), WAS (retro+ lenti)
B T NK
CD4 CD8
nTreg
WAS
CGD CGD
SCID
ADA
IL2RG
HSC
CLP
N MPLT
RBC
PERFORIN
Artemis
RAG-1/-2
FOXP3CD18
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Gene modified HSCT for treatment of Primary Immunodeficiency Disease
Gene transfervector
Autologous gene modifed
HSCT
+/- conditioning
Benefits:Autologous procedure (No rejection/ GVHD)Potential reduced toxicity vs ChemotherapyPotential lower morbidity and mortality vs ChemotherapyExploit natural selective advantage (primary immunodeficiency)Ability to deliver supranormal levels of protein or enzymes by design
Challenges:Efficient and stable gene transferAdequate dose of gene corrected HSCTEngraftment and expansion of gene corrected cellsEfficient regulated expression of therapeutic geneReduce the risk of insertional oncogenesis
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Stem cell isolation
Gene Therapy for PID
Cell growth
Reduced intensitychemotherapy
Infusion
Bone marrow harvest
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Current Trials for PID◦ ADA SCID◦ X-Linked SCID◦ Chronic Granulomatous Disease◦ Wiskott Aldrich Syndrome◦ Leukocyte Adhesion Defect
Gene Therapy
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Clinical Results
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Gene Therapy for Primary Immunodeficiencies
ADA-SCIDRecent/Completed trials
From: Stiehm’s Immune Deficiencies, 2014
Ongoing trials
DU3
EF1a Hu ADA
DU3ψWPRE
EFS-ADA Lentiviral Vector
University College LondonBobby GasparAdrian Thrasher
UCLA-NIHDonald B. KohnFabio Candotti
Centers
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ADA-SCID◦ Survival rate from ADA-SCID gene therapy has been 100% with
efficacy when comparing favorably with HCT with fully matched donor.
◦ Children's growth and bone age improved following treatment although were not normalized in all patients (Cavazzana-Calvo et al., 2012).
◦ Will soon be considered standard of care for patients without matched sibling donors.
ADA SCID
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Gene Therapy for Primary Immunodeficiencies
Lentiviral vector: CL20-I4-EF1a-hgc-OPTDU3+Ins
EF1a hgc-OPT
DU3+Ins
g-Retroviral vector: SRS11 SFgc
EF1a hgc
SIN-MPSV SIN-MPSV
WPRE
X-linked SCID
Completed trials
Ongoing trials
St. Jude Inclusion criteria • Age 3-12 mos• “Classic” SCID phenotype • No HLA-id sib donor• No conditioning
NIH
• Age >1 yr• Failed transplant • Atypical presentation• No HLA-id sib donor• 6 mg/kg Busulfan
London, ParisBoston, Cincinnati, Los Angeles
Inclusion criteria
• Age >3 mos• No HLA-id donor, no MUD• No conditioning
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SCID-X Linked ◦ Results from initial trials demonstrated clinical benefit but
supported recommendations for changes of insertion vectors and prognostic indicators Occurrence of leukemia due to insertional transactivation of
proto-oncogenes (MDS/EVI1 and LMO2) by elements present within the viral LTR
◦ Preliminary results rom an on-going 2010 multi-center (EU & US) trial involving 8 patients indicates similar clinical benefits and no adverse events although follow up is short.
The vector used in this trial was different (based on a SIN γ-
retrovirus in which the IL2RG gene is driven from an internal EF1α promoter)
Advances in Gene Therapy
http://dx.doi.org/10.1016/j.gene.2013.03.098
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Gene Therapy for Primary ImmunodeficienciesChronic Granulomatous Disease
Completed Trials
Ongoing trials
France, Germany, Switzerland, UKBoston, Los Angeles, NIH
DU3
Chim Hu GP91
DU3ψWPRE
Lentiviral vector: G1XCGD
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CGD ◦ Research ongoing since 1995◦ Variable clinical results◦ Newer viral vectors undergoing trials
Chronic Granulomatous Disease
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Wiskott-Aldrich Syndrome
Gene Therapy for Primary Immunodeficiencies
Completed Trials
Ongoing trials Lentiviral vector: W1.6wDU3
WASp WAS
DU3
WPRE
MilanParisLondonBoston
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Current Gene Therapy Trials for WAS
Lentiviral vector: W1.6w
Paris
London
Boston
Milan
• Severe phenotype• No HLA-id donor• No MUD (if <5 yo)• BU (12 mg/kg) + FLU conditioning• Rituximab ± ATG
DU3
WASp WAS
DU3
WPRE
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WAS◦ Similar issues with vector insertion
Occurrence of leukemia due to insertional transactivation of proto-oncogenes MDS/EVI1 and LMO2 by elements present within the viral LTR
Newer viral vectors undergoing trials
Wiskott-Aldrich Syndrome
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◦ Current multi-center trial in the UK, the US, France and Italy. Different vector for insertion Multicenter approach for gathering data on safety,
multi-lineage reconstitution, & clinical efficacy Uniform parameters of pre-conditioning and vector
quality
Further Research in WAS Gene Therapy
http://dx.doi.org/10.1016/j.gene.2013.03.098
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Promising results in animal models Potential human clinical trials
Leukocyte Adhesion Defect
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HSCT Gene Therapy
• HSCT gene therapy is efficacious in restoring immune functions in PID patients
• Pre-treatment conditioning is required for long-term engraftment of stem cells
• Adequate dose of transduced CD34+ cells is important
• Safety needs to be carefully balanced with vector design, nature of transgene and disease background
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• Progress with ADA SCID, X Linked SCID
• Preclinical studies and novel clinical trials using are very promising (XHIM, XLA, XLP)
• Safety and efficacy balance in comparison to allogeneic BMT
• When will gene therapy become a medicinal drug/standard of care?
Current Status of Gene Therapy
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The Future of Immunology?
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Sheridan C (2011). "Gene therapy finds its niche". Nature Biotechnology 29 (2): 121–128.Ferrua F, Brigida I, Aiuti A (2010). "Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency". Current Opinion in Allergy and Clinical Immunology 10 (6): 551–556.Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH (2014). "Gene Editing ofCCR5in Autologous CD4 T Cells of Persons Infected with HIV". New England Journal of Medicine 370 (10): 901–10
Bonagura VR et al. J Allergy Clin Immunol 2008;122(1):210-212Lucas M et al. J Allergy Clin Immunol 2010;125:1354-1360Berger M. Clin Immunol. 2004;112:1-7
Wasserman RL et al. JACI. 2012. HyQvia Prescribing Information, 2014 Berger M. Immunol Allergy Clin North Am. 2008;28:413-437. Bonilla FA, et al. Ann Allergy Asthma Immunol, 2005;94(5)(Suppl1):S1-S63 Skoda-Smith S, Torgerson TR, Ochs HD. Ther Clin Risk Manag. 2010;6:1-10. Younger ME, Aro L, Blouin W, et al. Nursing Guidelines for Administration of Immunoglobulin
Replacement Therapy. Journal of Infusion Nursing. 2013;36(1):58-68.
References
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Alessandro Aiuti MD, PhDHSR TigetMilan, IT
Elizabeth K. Garabedian, RN, MSLSNational Institutes of HealthNHGRI
M. Louise Markert, M.D., Ph.D.Professor of Pediatrics and ImmunologyDuke University Medical Center
Elyse Murphy BSN RNMedical Science Liaison Leader, Immunology Medical Affairs, CSL Behring
M. Elizabeth M. Younger CRNP, PhDAssistant Professor, PediatricsJohns Hopkins University School of Medicine Division of Pediatric Allergy and Immunology
Richard I Schiff, MD, PhD(Posthumous), Baxter
Thank You
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