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
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
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…
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
Chung K Y et al. JCO 2010;28:3485-3490 Pre-treatment 9 months
Lipson E J et al. Clin Cancer Res 2013;19:462-468
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.
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 2010. Tabernero ASCO 2013
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.
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.
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.
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
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)
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]
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]
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]
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.