Emerging Concepts and
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Transcript 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