Download Emerging Concepts and

Neil H. Segal, M.D., Ph.D.
Assistant Attending
Gastrointestinal Oncology Service and Immunotherapeutics Core
Memorial Sloan-Kettering Cancer Center

MedImmune: Research and consulting funds

Biothera: Research and consulting funds

BMS: Research funds

Pfizer: Research funds

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

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 microenvironment 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
Halama N et al. Cancer Res 2011;71:5670-5677
©2011 by American Association for Cancer Research

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
Pre-treatment
9 months
Chung K Y et al. JCO 2010;28:3485-3490
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 (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
©2010 by American Association for Cancer Research
Ralph C et al. Clin Cancer Res 2010;16:1662-1672

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
Anti-PD-1
Anti-PDL-1
Weak immune
response
Immune
ignorance
Poor clinical
response
Anti-PD-1
Strong immune
response
Tumor-Immune
equilibrium e.g.: Anti-PDL-1
PDL-1
Clinical
response
1) Anti-CTLA-1, Anti-KIR, Anti-CD137
2) Tumor destruction releases antigen to the immune
system e.g.: chemotherapy, ablation, radiation
Weak immune
response
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 AntiKIR (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.
Thank you