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

Disclosures

MedImmune: Research and consulting funds

Biothera: Research and consulting funds

BMS: Research funds

Pfizer: Research funds

IMT: 1891

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

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

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…

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

Halama N et al. Cancer Res 2011;71:5670-5677

©2011 by American Association for Cancer Research

PFS according to density scoring system

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

Chung K Y et al. JCO 2010;28:3485-3490

Partial response to Tremelimumab

Pre-treatment 9 months

Lipson E J et al. Clin Cancer Res 2013;19:462-468

Complete response to Nivolumab

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.

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

Ralph C et al. Clin Cancer Res 2010;16:1662-1672©2010 by American Association for Cancer Research

Clinical responses to Tremelimumab

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.

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.

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.

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

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

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)

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]

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]

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]

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.

Thank you