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Emerging Concepts and Therapies: Immunotherapy and GI malignancies

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Presentation on theme: "Emerging Concepts and Therapies: Immunotherapy and GI malignancies"— Presentation transcript:

1 Emerging Concepts and Therapies: Immunotherapy and GI malignancies
Neil H. Segal, M.D., Ph.D. Assistant Attending Gastrointestinal Oncology Service and Immunotherapeutics Core Memorial Sloan-Kettering Cancer Center

2 Disclosures MedImmune: Research and consulting funds
Biothera: Research and consulting funds BMS: Research funds Pfizer: Research funds

3 IMT: 1891

4 IMT: 2014 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

5 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 Higano Cancer Topalian NEJM 2012

6 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…

7 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:

8 PFS according to density scoring system
Halama N et al. Cancer Res 2011;71: ©2011 by American Association for Cancer Research

9 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 Brahmer JCO Topalian NEJM Tabernero ASCO 2013

10 Partial response to Tremelimumab
Pre-treatment months Chung K Y et al. JCO 2010;28:

11 Complete response to Nivolumab
Lipson E J et al. Clin Cancer Res 2013;19:

12 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 Das J Immunol 2006.

13 GE 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 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 Tabernero ASCO 2013

14 Clinical responses to Tremelimumab
Ralph C et al. Clin Cancer Res 2010;16: ©2010 by American Association for Cancer Research

15 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 Peng Mol Immunol 2008.

16 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.

17 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.

18 GI IMT paradigm Anti-PD-1 Anti-PDL-1 Strong immune response
Tumor-Immune equilibrium, e.g.: PDL-1 Clinical response Anti-PD-1 Anti-PDL-1 Weak immune response Immune ignorance Poor clinical response

19 GI IMT paradigm Anti-PD-1 Anti-PDL-1 Weak immune response
Strong immune response Tumor-Immune equilibrium e.g.: PDL-1 Clinical response Anti-PD-1 Anti-PDL-1 Anti-CTLA-1, Anti-KIR, Anti-CD137 Tumor destruction releases antigen to the immune system e.g.: chemotherapy, ablation, radiation Weak immune response

20 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” (NCT )

21 Clinical 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 ]

22 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” [NCT ]

23 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” [NCT ]

24 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.

25 Thank you

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