Presentation on theme: "Emerging Concepts and Therapies: Immunotherapy and GI malignancies"— Presentation transcript:
1Emerging Concepts and Therapies: Immunotherapy and GI malignancies Neil H. Segal, M.D., Ph.D.Assistant AttendingGastrointestinal Oncology Service and Immunotherapeutics CoreMemorial Sloan-Kettering Cancer Center
2Disclosures MedImmune: Research and consulting funds Biothera: Research and consulting fundsBMS: Research fundsPfizer: Research funds
4IMT: 2014 PD-1 = activated T-cells Blocks T-cell activation Down-regulates unwanted immunityPD-L1 = Non-hematopoietic tissuesInduced by local inflammation, gIFNCorrelates w/ poor outcome in cancerCTLA-4 = Effector and regulatory T-cellsBinds B7-1/-2 on APCsTurns “OFF” T-cellsKIR = NK cellsRecognizes MHC lossTurns “ON” the effector cellCD137 = activated T-cellsUnregulated during T-cell activation
5Immunotherapy in cancer Ipilimumab (Anti-CTLA-4)676 melanoma patientsIpilimumab ± gp100 vs. gp100. OS = 6.5 > 10 monthsSipuleucel-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 monthsNivolumab (Anti-PD-1)Phase I trial, including melanoma. RR 41%Hodi NEJM Higano Cancer Topalian NEJM 2012
6Immunotherapy in GI cancer GI cancers are immunogenic!!!Present diverse challenges and opportunities for IMTMay develop in an immune suppressive micro-environment that is permissive for commensal microbiotaUsually not associated with carcinogens and high mutation burden, with exceptions…
7Colorectal Cancer: Pathology Tumors associated with dense TILs have better prognosis*DNA mismatch repair deficient tumors are:Associated with +++TILsDevelop immune response to frame-shift peptidesHave better outcome in early stagesHalama N et al. Cancer Res 2011;71:
9Colorectal Cancer: IMT Anti-CTLA-4/ TremelimumabPhase II trial of 47 CRC patients (15 mg/kg Q12w)1 PR*, lasted 15 months45% patients alive at 6 monthsAnti-PD-1/ Nivolumab2 trials, included 20 CRC patients (1 dose/ Q2W)1 CR*Anti-PDL-1/ MPDL3280A (Q2W)Response observedChung et al. JCO Brahmer JCO Topalian NEJM Tabernero ASCO 2013
10Partial response to Tremelimumab Pre-treatment monthsChung K Y et al. JCO 2010;28:
11Complete response to Nivolumab Lipson E J et al. Clin Cancer Res 2013;19:
12Gastric Cancer: Pathology Frequently associated with H. Pylori infectionInfection of H. Pylori into the gastric mucosa induces infiltration of T-cells, B-cells, macrophages, and neutrophilsGastric epithelial cell lines exposes to H. pylori up-regulate PD-L1D’Elios Eur J Immun Das J Immunol 2006.
13GE Cancer: IMT Anti-CTLA-4/ Tremelimumab Anti-PDL-1/ MPDL3280A (Q2W) 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 pain12-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 observedRalph Clin Can Res Tabernero ASCO 2013
15Hepatocellular Cancer: Pathology Multicentric HCC occurs in 20-60% of patients with HCC after resection and associated with continuous viral infection and chronic inflammationPD-1 expression on HBV/HCV-specific T cells is associated with T-cell dysfunction/ exhaustionTumor PDL-1 expression is associated with vascular invasion and poor survivalGao Clin Can Res Peng Mol Immunol 2008.
16Hepatocellular Cancer: IMT Anti-CTLA-4/ TremelimumabPhase 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.
17Pancreas Cancer May be associated with TILs and TAMs Tumor-associated antigens are present and may be detected, e.g.: MesothelinVaccination with GVAX (GM-CSF–secreting tumor cells):Induction of mesothelin-specific T-cell responsesMay correlate with improved outcomeThomas JEM 2004.
19GI IMT paradigm Anti-PD-1 Anti-PDL-1 Weak immune response Strong immune responseTumor-Immune equilibrium e.g.: PDL-1Clinical responseAnti-PD-1Anti-PDL-1Anti-CTLA-1, Anti-KIR, Anti-CD137Tumor destruction releases antigen to the immune system e.g.: chemotherapy, ablation, radiationWeak immune response
20Clinical 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” (NCT )
21Clinical Trials: anti-CD137 Anti-CD137 inc. CRC:“A Phase 1 Study of the Safety, Tolerability, Pharmacokinetics and Immunoregulatory Activity of Urelumab (BMS ) in Subjects with Advanced and/or Metastatic Solid Tumors and Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma (B-NHL)” [NCT ]
22Clinical 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” [NCT ]
23Clinical 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” [NCT ]
24Summary 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.