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Cytokines in Cancer Immunotherapy
Kim Margolin, M.D.University of Washington
Fred Hutchinson Cancer Research CenterSeattle Cancer Care Alliance
iSBTc Immunology PrimerOctober 1, 2010
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Presenter disclosure information• Kim Margolin, M.D., UW/FHCRC/SCCA
• No financial support for research except site PI budget support– BMS– GSK– Lilly– Pfizer– Roche
• DMC– Cougar/J and J– Medimmune
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Immunobiology of Cytokines
For discussion– Structure/function
relationships– Cellular source/stimuli for
synthesis/secretion– Target cell(s)/receptor
structure– Signaling induced by
cytokine binding– Preclinical applications– Cytokine gene
transfer/vaccine– Clinical application/status
Not for discussion– Cytokines/polymorphisms in
pathogenesis• Malignancy• Autoimmune disease
– Cytokine-directed therapies for nonmalignant conditions
– Complex interactive cytokine networks, innate
– Alternative structures (immunotoxins, immunocytokines)
– Intratumoral delivery
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Generic cytokinesignaling
Gene expression
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Cytokinereceptorfamilies
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GM-CSF as immunotherapy
• Cells of origin– Th1, Th2 – Others include epithelial, fibroblast, tumor
• Target cell: immature DC (& myeloid progenitor)• Biological functions
– Stimulation of T cell immunity via effect on APC– Myeloid cell proliferation, differentiation
• Clinical development– Hematopoietic support– Not a potent stand-alone cytokine in cancer– Adjuvant for melanoma: (-) results+/- peptide vaccine– Immunocytokine in prostate cancer DC product– Transgenic expression (GVAX) [and other cytokines]
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GM-CSF transgenic tumor “GVAX”
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Interferons
• Type I– α: from neutrophils, m– β: from fibroblasts, epithelial cells
• Type II -IFN, type 1, from T, NK cells
• Immunomodulatory effects– MHC class I/II upregulation– Modulation of T/NK cell cytolytic activity– Modulation of macrophage/DC function– Decreased Treg/increased Th1
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• Direct effects on tumor cells– MHC upregulation– Antiproliferative/pro-apoptotic effects
• Anti-angiogenic effects– IP-10– Thrombospondin
Interferons (cont.)
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IFN-Signaling
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IFN- Signaling
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Relapse-freesurvival
Overall survival
IFN autoimmunity/ adjuvant benefit in melanoma
Gogas et al NEJM 2006
IFN in melanoma, other malignancies remains a work in progress
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Interleukin-2
• Short chain type I cytokine• Four -helical bundles• Produced by activated T cells• TCR/CD3 engagement plus
CD28 ligation required • Main targets are T, NK cells• Stimulates immune responses
and prevents tolerance• Also downregulates immune
response: role in Tregdevelopment/activity
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Interleukin-2• “T cell growth factor”• Produced by Th1 cells• Many cell types express IL-2R
– B, NK/NKT, monocytes– Affinity, functions depend on subunit αβ expression
• Signaling – JAK-STAT>– MAPK– PI3K
• Proliferation, cytotoxicity
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IL-2 Signaling
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In Vivo Effects of IL-2• Induction of multiple cytokines
– TNF, interferon-gamma, GM-CSF, M-CSF, G-CSF, IL-4, IL-5, IL-6, IL-8, IL-10
• Increase in soluble IL-2r• Lymphopenia followed by rebound• Increased NK activity (during rebound)• Increased CD25, HLA-DR expression on T-cells• Decreased PBMC proliferative responses• Tissue infiltration by lymphocytes• Eosinophilia• Neutrophil chemotaxis defect
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Pioneering NCIstudies
• Biology/source– T cell growth factor– Jurkat source – Recombinant E. coli
• Preclinical models– Toxicities from capillary leak– Toxicities vary by species– Dose-dependent activity
• Early clinical studies+LAK
• Supportive role in adoptivecell-Rx strategies
Extramural IL-2 studies
In solid tumors– With LAK cells– Single agent high/low doses– With -IFN– With other cytokines– With chemotherapy– Toxicity modulation– Biological predictors of benefit
• In heme malignancies– Preclinical activity– Clinical benefits not achieved
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Prob
. of C
ontin
uing
Res
pons
e
Durability of Responses to HD IL-2 in Melanoma
Months
CR
PR
CR + PR
0.0
0.2
0.4
0.6
0.8
1.0
120
108
96847260483624120
Responses in melanoma
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Responses in renal cancer
Klapper, JA et al. Cancer (2008)
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IL-2 Grade 3-4 Toxicity
NCI-SB HD IL-2 CWG HD IL-2Median Doses per Course
12 (28) 68% (19 doses)
Death 0 1%
Hypotension 36.4% 56.8%
Pulmonary 4.2% 13.7%
CNS orientation 10.2% 14.7%
CNS consciousness 2.5%
Infection 2.8% 3.2%
Nausea/vomiting 13.4% 9.5%
Diarrhea 9.2%
Hyperbilirubinemia 3.2% 11.6%
ALT 3.2%
Creatinine > 8.0 mg/dL 1.1% 13.7% (gr 3-4)
Oliguria (< 80 ml/8h) 12%
Atrial Arrhythmia 4.2% 8.4% (all cardiac)
Malaise 20.5% 3.2%
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Incidence of Severe Toxicities in Patients Treated with High-Dose Bolus IL-2
14Death
2921Thrombocytopenia
36Infection
514Arrhythmias (all grades)
26Myocardial injury (ischemia, infarction, myocarditis)
2832CNS
1921Hepatic (hyperbilirubinemia)
1014Renal (creatinine elevation)
1017Pulmonary (dyspnea)
5774Hypotension
Rosenberg et al (1994)N = 149
(% of IL-2 courses)
Fyfe et al (1995)N = 255
(% of patients)Grade 3 or 4 Toxicity
Incidence
14Death
2921Thrombocytopenia
36Infection
514Arrhythmias (all grades)
26Myocardial injury (ischemia, infarction, myocarditis)
2832CNS
1921Hepatic (hyperbilirubinemia)
1014Renal (creatinine elevation)
1017Pulmonary (dyspnea)
5774Hypotension
Rosenberg et al (1994)N = 149
(% of IL-2 courses)
Fyfe et al (1995)N = 255
(% of patients)Grade 3 or 4 Toxicity
Incidence
Severe toxicities of high-dose IL-2
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How does high-dose IL-2 work?
Panelli MC et al Genome Biology 2002
Multiple hypotheses from animal data, but rigorous human data lacking.
Gene expression profiling on FNA of tumor, serial PBMC in melanoma patients on HD-IL-2
HD IL-2
Tumor-site inflammation
Activation of
Monocytes
Chemokine production;Immune cell recruitment
Activation of
NK cells
Adaptive immune response
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Phase III Trial of High-Dose IL-2 ± Peptide Vaccine in Patients With Metastatic Melanoma
• Pts with stage IV or locally advanced stage III cutaneous melanoma
• HLA-A*0201 positive
(N=185)
High-dose IL-2 720K IU/kg/dose IV every 8 hours x 12
Repeat every 3 weeks(N=94)
Vaccine ([gp100:209-217(210M)] subcutaneous d1 q3w) +
High-dose IL-2 (as above)(N=91)
• Primary endpoint: RR• Secondary endpoints: toxicity, PFS, quality of life, and
immunologic monitoring• Central HLA typing, pathology review, and blinded response
assessment performed at the National Institutes of Health
Schwartzentruber. ASCO. 2009 (abstr CRA9011);
Eligibility CriteriaRANDOMIZE
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High-Dose IL-2 ± Peptide Vaccine: Results
Reproduced with permission from Schwartzentruber. ASCO. 2009 (abstr CRA9011).
PFS OS
Treatment RR* (%) PFS (mos) OS (mos)High-dose IL-2 9.7 1.6 12.8High-dose IL-2 + vaccine 22.1 2.9 17.6
*Investigator assessment.
IL-2 + gp 100IL-2 AloneIL-2 + gp 100
IL-2 Alone
Tim
e-to
-Pro
gres
sion
Sur
viva
l
Ove
rall
Surv
ival
0.0
0.8
0.6
0.4
0.2
0.0
0.0
0.8
0.6
0.4
0.2
0.00 1 2 3 4 5 6 0 1 2 3 4 5 6
Time (Years) Time (Years)
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Regimen RR (%)
TBI 12 Gy 72
TBI 2 Gy 52
NMA 48.8
Adoptive T-Cell Therapy and Intensive Myeloablative Chemoradiation: Results
Dudley J Clin Oncol. 2008
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IL-2: Current and future
• Structural alterations• Toxicity modulation without loss of activity• Combinations
– Anti-angio/cytotoxics/STIs/other cytokines– Vaccines (melanoma peptides enhanced IL-2)
• Greater insight into mechanisms– Renal “Select” trial to validate prior observations
re: histology, hypoxia genes– Melanoma “Selection” trial to study immune
polymorphisms, tumor gene expression– Autophagy? (Lotze)
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InterleukinInterleukin--44
Pleomorphic Th2 cytokine Pleomorphic Th2 cytokine Net effects depend on milieuNet effects depend on milieu
–– Mainly a B cellMainly a B cell--stimulatorstimulator–– Inhibits nonInhibits non--specific NK activity specific NK activity –– Enhances other adaptive immune functionsEnhances other adaptive immune functions Growth factor for Th2Growth factor for Th2 Promotes proliferation, cytotoxicity of CTLPromotes proliferation, cytotoxicity of CTL Stimulates MHC class II expressionStimulates MHC class II expression Contributes to DC maturationContributes to DC maturation Enhances mEnhances mΦΦ tumorcidal activitytumorcidal activity
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IL-4 Signalling
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Promising preclinical data, especially Promising preclinical data, especially transgenic secretion by tumortransgenic secretion by tumor
Clinical experience limitedClinical experience limited–– Studied like ILStudied like IL--2 at MTD2 at MTD–– Unfavorable therapeutic indexUnfavorable therapeutic index
Used routinely to elicit iUsed routinely to elicit i--moDC from PBMCmoDC from PBMC–– Used Used ex vivoex vivo w/GMw/GM--CSFCSF–– Shares some structure, function with ILShares some structure, function with IL--1313
InterleukinInterleukin--44
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ILIL--4 and IL4 and IL--1313
SimilaritiesSimilarities–– Predominantly antiPredominantly anti--
inflammatory effectsinflammatory effects–– Favor ThFavor Th22 responsesresponses–– Partially common receptorPartially common receptor–– Promotes Ig class switchPromotes Ig class switch–– Used w/ GMUsed w/ GM--CSFCSFmoDCs moDCs
Differences Differences –– ILIL--13 activity on 13 activity on
monocyte/mmonocyte/mΦΦ cellscells–– ILIL--13 lacks B, T cell effects13 lacks B, T cell effects
ILIL--13 receptors on tumor 13 receptors on tumor cells, especially gliomacells, especially glioma–– Immunotoxins Immunotoxins –– Chimeric T cell Ag receptorChimeric T cell Ag receptorAssortment of
receptor subunits depend on cell type
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c
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Trikha, M. et al. Clin Cancer Res 2003
Fig. 1
IL-6 is pleiotropic
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ILIL--66 Tumor sourceTumor source
–– Unfavorable prognostic for renal cancerUnfavorable prognostic for renal cancer–– Important growth factor for myelomaImportant growth factor for myeloma–– Mediates paraneoplastic thrombocytosisMediates paraneoplastic thrombocytosis
Adaptive systemAdaptive system–– B cell growth/differentiationB cell growth/differentiation–– CTL differentiation, Type 2 responsesCTL differentiation, Type 2 responses
Preclinical data suggested antitumor activityPreclinical data suggested antitumor activity Clinical dataClinical data
–– Too toxicToo toxic–– ?tumor promotion?tumor promotionBBlockade may be therapeutic lockade may be therapeutic
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IL-6 signaling
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Dong 2008
Examples of cytokine-mediated counterregulation
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c cytokines
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IL-7Signaling/gene expression
JAK 1,3 STAT 5PI3K mTOR activation
Regulation contrasts with IL-2, IL-15Unique to IL-7 is receptor downregulationIL-7 accumulates during lymphopenia due to utilization
Mediates homeostatic expansion of naïve cells during lymphopenia (greatest clinical potential, possibly with IL-15, IL-21)
Kaech, Nat Imm 2003
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IL-15• Unique c cytokine—complexes with
receptor from cell of origin, then signals target cell
• With IL-2 and IL-7 in c cytokine family promoting T cell growth, differentiation
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IL-2 and IL-15 compared
• IL-2– Activated T, B express
high-affinity receptor
– Prolif/differentiation NK, T, B
– Promotes activation-induced cell death
– Maintenance of Treg
– -/- KO develops autoimmunity
• IL-15– Produced by DC, monos– Surface-bound on
DC/mono receptors onNK, CD8a1 cells
– Promotes proliferation NK, T, B, memory CD8
– Inhibits AICD– Does not support Treg
– -/- KO is lymphopenic
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Waldmann Nature Reviews Immunology 2006
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ILIL--1212
Link between innate, adaptive immune responseLink between innate, adaptive immune response–– Receptors on variety of immune cellsReceptors on variety of immune cells–– Induces IFNInduces IFN--, a prototypical type I cytokine, a prototypical type I cytokine
Potent inducer of counterregulatory type 2 cytokinesPotent inducer of counterregulatory type 2 cytokines–– Emerged in clinical trials for advanced malignancyEmerged in clinical trials for advanced malignancy–– Schedules and doses may be manipulatedSchedules and doses may be manipulated
Clinical potentialClinical potential–– Vaccine adjuvantVaccine adjuvant–– Induction of antiInduction of anti--angiogenesisangiogenesis–– In combinations e.g. w/In combinations e.g. w/--IFN, ILIFN, IL--2?2?
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IL-12 andinnate/
adaptiveimmunesystem
IL-12family
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-y-y-y pp
pppp
Jak3pp
Jak1pp
Stat4 -y pps-
-y-y-y pp
pppp
Jak2p Jak2pp
Tyk2p Tyk2pp
y-y-pp
pp
IL-12 IL-2
1 2
c
Stat3 -y ps- Stat3 -y pStat3Stat3 -y pps-Stat1 -y ps- Stat1 -y pStat1Stat1 -y pps-
Stat5 -y ps- Stat5 -y pStat5Stat5 -y pps-
Stat5 -y ps- Stat5 -y pStat5Stat5 -y pps-
Stat1 -y ps- Stat1 -y pStat1Stat1 -y pps-Stat3 -y ps- Stat3 -y pStat3Stat3 -y pps-
Jak/Stat Signaling: IL-12 versus IL-2
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IL-21 is a pleiotropic cytokine
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Interleukin-21 and its receptor
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Clinical activity of IL-21
1 CR, 11 SD among 24 melanoma patients
4 PR, 13 SD among 19 renal cancer patients
Thompson JA et al. J Clin Oncol 2008
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Other Clinical Trials of IL-21
Disease Type Trial DesignMelanoma 1Phase I: Alternative schedules
5+9 schedule x 3 and 3x/week2Phase IIa: 5+9 schedule x 33NCIC PHASE II: 5+9 schedule x 3, q 8 weeksTreatment-naive; bulky disease excluded
Renal cell Cancer
IL-21 plus Sunitinib
Lymphoma 4IL-21 and Rituximab in Relapsed/Refractory Indolent Lymphoma
1Davis ID. Clin Cancer Res 2007 2Davis ID. Clin Cancer Res 2009 3Petrella T et al. ASCO 2010 4Timmerman JM et al. ASCO 2008
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IL-10: a Th2counter-regulatorycytokine
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Thank youThank you
Any questions?Any questions?