neil h. segal, m.d., ph.d. assistant attending gastrointestinal oncology service and...
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Emerging Concepts and Therapies:
Immunotherapy and GI malignancies
Neil H. Segal, M.D., Ph.D.Assistant AttendingGastrointestinal Oncology Service and Immunotherapeutics Core Memorial Sloan-Kettering Cancer Center
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Disclosures
MedImmune: Research and consulting funds
Biothera: Research and consulting funds
BMS: Research funds
Pfizer: Research funds
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IMT: 1891
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PD-1 = activated T-cells Blocks T-cell activation Down-regulates unwanted immunity
PD-L1 = Non-hematopoietic tissues Induced by local inflammation, gIFN Correlates w/ poor outcome in cancer
CTLA-4 = Effector and regulatory T-cells Binds B7-1/-2 on APCs Turns “OFF” T-cells
KIR = NK cells Recognizes MHC loss Turns “ON” the effector cell
CD137 = activated T-cells Unregulated during T-cell activation Turns “ON” the effector cell
IMT: 2014
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Immunotherapy in cancer
Ipilimumab (Anti-CTLA-4) 676 melanoma patients Ipilimumab ± gp100 vs. gp100. OS = 6.5 > 10 months
Sipuleucel-T (Autologous APCs + prostatic acid phosphatase linked to GM‑CSF) 225 Prostate Ca. patients (integrated results from 2
trials) Sipuleucel-T vs. Placebo. MS 18.9 > 23.2 months
Nivolumab (Anti-PD-1) Phase I trial, including melanoma. RR 41%
Hodi NEJM 2010. Higano Cancer 2009. Topalian NEJM 2012
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Immunotherapy in GI cancer
GI cancers are immunogenic!!!
Present diverse challenges and opportunities for IMT
May develop in an immune suppressive micro-environment that is permissive for commensal microbiota
Usually not associated with carcinogens and high mutation burden, with exceptions…
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Colorectal Cancer: Pathology
Tumors associated with dense TILs have better prognosis*
DNA mismatch repair deficient tumors are: Associated with +++TILs Develop immune
response to frame-shift peptides
Have better outcome in early stages Halama N et al. Cancer Res 2011;71:5670-5677
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Halama N et al. Cancer Res 2011;71:5670-5677
©2011 by American Association for Cancer Research
PFS according to density scoring system
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Colorectal Cancer: IMT
Anti-CTLA-4/ Tremelimumab Phase II trial of 47 CRC patients (15 mg/kg Q12w) 1 PR*, lasted 15 months 45% patients alive at 6 months
Anti-PD-1/ Nivolumab 2 trials, included 20 CRC patients (1 dose/ Q2W) 1 CR*
Anti-PDL-1/ MPDL3280A (Q2W) Response observed
Chung et al. JCO 2010. Brahmer JCO 2010. Topalian NEJM 2012. Tabernero ASCO 2013
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Chung K Y et al. JCO 2010;28:3485-3490
Partial response to Tremelimumab
Pre-treatment 9 months
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Lipson E J et al. Clin Cancer Res 2013;19:462-468
Complete response to Nivolumab
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Gastric Cancer: Pathology
Frequently associated with H. Pylori infection
Infection of H. Pylori into the gastric mucosa induces infiltration of T-cells, B-cells, macrophages, and neutrophils
Gastric epithelial cell lines exposes to H. pylori up-regulate PD-L1
D’Elios Eur J Immun 1997. Das J Immunol 2006.
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GE Cancer: IMT
Anti-CTLA-4/ Tremelimumab Phase II trial of 18 patients (2nd line) (15 mg/kg Q12w) 1 PR* after eight cycles (25.4 months) 4 SD & clinical benefit: improvement in weight and
pain 12-month survival rate of 33% (95% CI, 14-54%)
Improved survival was associated with anti-CEA T-cells immunity: 17.1 vs. 4.7 months (P = 0.004).
Anti-PDL-1/ MPDL3280A (Q2W) Response observed
Ralph Clin Can Res 2010. Tabernero ASCO 2013
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Ralph C et al. Clin Cancer Res 2010;16:1662-1672©2010 by American Association for Cancer Research
Clinical responses to Tremelimumab
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Hepatocellular Cancer: Pathology
Multicentric HCC occurs in 20-60% of patients with HCC after resection and associated with continuous viral infection and chronic inflammation
PD-1 expression on HBV/HCV-specific T cells is associated with T-cell dysfunction/ exhaustion
Tumor PDL-1 expression is associated with vascular invasion and poor survival
Gao Clin Can Res 2009. Peng Mol Immunol 2008.
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Hepatocellular Cancer: IMT
Anti-CTLA-4/ Tremelimumab Phase II trial of 17 HCV patients (15 mg/kg
Q12w)
RR = 17.6%. (3/17 PR) TTP = 6.5 months (95% CI 3.95–9.14)
Decrease in HCV viral load was associated with enhanced anti-HCV immune response.
Sangro J Hepato 2012.
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Pancreas Cancer
May be associated with TILs and TAMs
Tumor-associated antigens are present and may be detected, e.g.: Mesothelin
Vaccination with GVAX (GM-CSF–secreting tumor cells): Induction of mesothelin-specific T-cell
responses May correlate with improved outcome
Thomas JEM 2004.
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Strong immune response
Tumor-Immune
equilibrium, e.g.: PDL-1
Clinical response
Weak immune response
Immune ignorance
Poor clinical response
Anti-PD-1Anti-PDL-1
GI IMT paradigm
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Strong immune response
Tumor-Immune
equilibrium e.g.: PDL-1 Clinical
response
Weak immune response
Anti-PD-1Anti-PDL-1
1)Anti-CTLA-1, Anti-KIR, Anti-CD137
2)Tumor destruction releases antigen to the immune system e.g.: chemotherapy, ablation, radiation
GI IMT paradigm
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Clinical Trials: anti-CTLA-4
Ipilimumab in Gastric or GEJ Cancer:
“A Randomized, Open-label, Two-arm Phase II Trial Comparing the Efficacy of Sequential Ipilimumab Versus BSC Following First-line Chemotherapy in Subjects With Unresectable Locally Advanced/Metastatic Gastric or GEJ Cancer” (NCT01585987)
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Clinical Trials: anti-CD137
Anti-CD137 inc. CRC:
“A Phase 1 Study of the Safety, Tolerability, Pharmacokinetics and Immunoregulatory Activity of Urelumab (BMS-663513) in Subjects with Advanced and/or Metastatic Solid Tumors and Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma (B-NHL)” [NCT01471210]
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Clinical Trials: anti-PD-1/ KIR
Anti-PD-1 + Anti-KIR inc. CRC and HCC:
“A Phase I Dose Escalation and Cohort Expansion Study of the Safety, Tolerability and Efficacy of Anti-KIR (Lirilumab) Administered in Combination with Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors” [NCT01714739]
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Clinical Trials: anti-PDL-1
Anti-PDL-1 inc. GE, Pancreas Cancer, HCC:
“A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 in Subjects With Advanced Solid Tumors” [NCT01693562]
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Summary
GI cancers are recognized by the immune system: Colorectal Cancer, Gastric Cancer, Pancreas Cancer and
Hepatocellular Cancer.
Monotherapies may not work well in GI cancers without strong baseline immunogenicity.
GI cancers may be targeted by an augmented immune response with clinical benefit in a subset of patients.
We need to: Identify patients who respond to immunotherapy, learn why, then
focus our future trial designs. study combination approaches that stimulate the immune system
(with antigen) and augment the immune response.
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Thank you