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Neil H. Segal, M.D., Ph.D. Assistant Attending Gastrointestinal Oncology Service and Immunotherapeutics Core Memorial Sloan-Kettering Cancer Center.

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Presentation on theme: "Neil H. Segal, M.D., Ph.D. Assistant Attending Gastrointestinal Oncology Service and Immunotherapeutics Core Memorial Sloan-Kettering Cancer Center."— Presentation transcript:

1 Neil H. Segal, M.D., Ph.D. Assistant Attending Gastrointestinal Oncology Service and Immunotherapeutics Core Memorial Sloan-Kettering Cancer Center

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

3

4  PD-1 = activated T-cells  Blocks T-cell activation  Down-regulates unwanted immunity  PD-L1 = Non-hematopoietic tissues  Induced by local inflammation,  IFN  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

5  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  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  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 ©2011 by American Association for Cancer Research

9  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 Chung K Y et al. JCO 2010;28: Pre-treatment 9 months

11 Lipson E J et al. Clin Cancer Res 2013;19:

12  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  Anti-CTLA-4/ Tremelimumab  Phase II trial of 18 patients (2 nd 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 Ralph C et al. Clin Cancer Res 2010;16: ©2010 by American Association for Cancer Research

15  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  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  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 Strong immune response Tumor-Immune equilibrium, e.g.: PDL-1 Clinical response Weak immune response Immune ignorance Poor clinical response Anti-PD-1 Anti-PDL-1

19 Strong immune response Tumor-Immune equilibrium e.g.: PDL-1 Clinical response Weak immune response Anti-PD-1 Anti-PDL-1 1)Anti-CTLA-1, Anti-KIR, Anti-CD137 2)Tumor destruction releases antigen to the immune system e.g.: chemotherapy, ablation, radiation

20 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 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 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 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  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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