Overview of immune aspects- endometrial / cervical cancer-
Hans NijmanLisban GCIG meeting, Thursday October 27th, 2016
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Mellman, Immunity, 2013
Immune response against cancer
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Tumor Infiltrating T cells
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Treatment selection based on immune resistance
Ribas et al
Hot tumors
Cold tumors
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
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Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
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Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
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CD8+ cells CD103+ cells
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
8Workel&Komdeur et al. Eur J Cancer. 2016 Jun;60:1-11. doi: 10.1016/j.ejca.2016.02.026.
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
9Komdeur&Wouters et al. Oncotarget. In print.
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
10Komdeur&Wouters et al. Oncotarget. In print.
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
11Komdeur&Wouters et al. Oncotarget. In print.
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
12Komdeur&Wouters et al. Oncotarget. In print.
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Treatment selection based on immune resistance
Ribas et al
Hot tumors
Cold tumors
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Releasing the breakes on Cancer Immunotherapy
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Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Pembrolizumab in tumors with mismatch-repair deficiency
• Phase II study
• Patients with treatment refractory progressive metastatic cancer,
in 3 groups:
– Mismatch repair deficient colorectal adenocarcinomas (N=11)
– Mismatch repair proficient colorectal adenocarcinomas (N=21)
– Mismatch repair deficient non colorectal cancer (N=9)
• 2 patients with endometrial cancer in this group
• Pembroluzimab IV, 10mg/kg every 14 days
15Le et al, NEJM 2015
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Pembrolizumab in tumors with mismatch-repair deficiency
16Le et al, NEJM 2015
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Pembrolizumab in tumors with mismatch-repair deficiency
Objective RR
MMR-deficientColorectal
4/10 (40%)
MMR-proficientColorectal
0/18 ( 0%)
MMR-deficientNon-colorectal
5/7 (71%)
• 2 casus of EC: 1 CR & 1 PR
17Le et al, NEJM 2015
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Mean somatic mutations per tumor (whole exome sequencing)
MMR- proficient: 73 MMR- deficient : 1782
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Single nucleotide variants introduce neo-epitopes
Sahin et al, Current opinion immunology, 2016
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Mutant-antigen repertoire in human cancers
Alexandrov et al,Nature 2013
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
EC – Four moleculair subtypes
Kandoth et al., Nature 2013
Copy number high(serous-like)
Copy number low(endometrioid)
MSI(hyper-mutated)
POLE(ultra-mutated)
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Molecular classification of endometrial cancer
• The Cancer Genome Atlas Network:
– Integrated genomic, transcriptomic and proteomic characterization of
373 endometrial carcinomas.
TCGA, Nature 2013
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
POLE-mutations
• POLE: DNA polymerase epsilon.
– Involved in proofreading of DNA during DNA replication
• 7-12% of EC
• High frequency of base substitution mutations
• Strong association with endometrioid histology and high
grade
• Excellent prognosis, but why?
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Hypothesis
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Do POLE mutant endometrial cancers show increased immunogenicity?
• Analysis of immune infiltration in 150 tumor samples from
PORTEC 1 and 2, LUMC and UMCG
25Van Gool, CCR 2015
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
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Increased density of intratumoral CD8+ lymphocytes in POLE mutants
Van Gool and Eggink et al , CCR 2015
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Conclusions on POLE & MSI tumors
• High immune cell infiltration of POLE-mutant and MSI
tumors.
• High PD-1 and PD-L1 expression in POLE-mutant and MSI
tumors.
• Suggests sensitivity to checkpoint inhibition for these
subgroups.
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Treatment selection based on immune resistance
Ribas et al
Hot tumors
Cold tumors
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Antigens for vaccine development• Examples of vaccination
trials
– Survivin in EC (immune response
in 25% ptn) / J. Immunotherapy
2015
– WT1 in EC (immune response in 3
out of 4) Anticancer Research
2013
– P53 in OC (immune response in
80% of the ptn).
Schumacher et al, Cur Op Immunol 2013
Neo antigens
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Mellman, Immunity, 2013
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Melero et al, Nature Reviews Cancer 2015
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
UMCG, Dept. of Gyn. OncologyThaline Prins Henriette ArtsAnouk Terwindt Refika YigitFenne Komdeur Maaike OonkFlorine Eggink Marian MouritsMarco Versluis Ate van der ZeeKim BrunekreeftStephanie van de Wall Harry G. Klip Hagma Workel Annechien Plat Joyceposition for PhD student (MD)
Bea Wisman Marco de BruynValerie Wiersma
UMCG, Dept. of HematologyEdwin Bremer
University of Würzburg, GermanyHarald Wajant
University of Exeter, UK Paul Eggleton
When I said I, I meant we. When I said we, I meant them:
UMCG, Dept. of VirologyToos Daemen
UMCG, Dept. of Med. OncologySteven de Jong & Marcel van VughtAn Reyners & Hilde Jalving
University of Southampton, UKTim Elliott
LUMC, NLTjalling BosseMariette van PoelgeestVincent SmitCarien CreutzbergSjoerd van der Burg
ENITEC consortium, ESGO
TRANSPORTEC consortium
University of Oxford, UK David Church
Aduro Andrea v. Elsas & Hans v. Eenenaam
TRON & GANYMED Ugur Sahin & Ozlem Türeci
UMCG, Dept. of PathologyHarry Hollema & Evelien Duiker
UMCG, Dept. of GeneticsPieter van de Vlies & Kim de Lange
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016
Gynecologic Cancer InterGroupTranslational Research BrainstormingOctober 2016