Overview of immune aspects - endometrial / cervical cancer- Hans - PowerPoint PPT Presentation

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Overview of immune aspects - endometrial / cervical cancer- Hans Nijman Lisban GCIG meeting, Thursday October 27th, 2016

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Immune response against cancer Mellman, Immunity, 2013

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Tumor Infiltrating T cells

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Treatment selection based on immune resistance Hot tumors Cold tumors Ribas et al

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 5

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 6

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 CD8+ cells CD103+ cells 7

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 8 Workel&Komdeur et al. Eur J Cancer. 2016 Jun;60:1-11. doi: 10.1016/j.ejca.2016.02.026.

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 9 Komdeur&Wouters et al. Oncotarget. In print.

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 10 Komdeur&Wouters et al. Oncotarget. In print.

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 11 Komdeur&Wouters et al. Oncotarget. In print.

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 12 Komdeur&Wouters et al. Oncotarget. In print.

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Treatment selection based on immune resistance Hot tumors Cold tumors Ribas et al

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Releasing the breakes on Cancer Immunotherapy 14

Gynecologic Cancer InterGroup Translational Research Brainstorming October 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 Le et al, NEJM 2015 15

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Pembrolizumab in tumors with mismatch-repair deficiency Le et al, NEJM 2015 16

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Pembrolizumab in tumors with mismatch-repair deficiency • 2 casus of EC: 1 CR & 1 PR Objective RR MMR-deficient 4/10 (40%) Colorectal MMR-proficient 0/18 ( 0%) Colorectal MMR-deficient 5/7 (71%) Non-colorectal Le et al, NEJM 2015 17

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Mean somatic mutations per tumor (whole exome sequencing) MMR- proficient: 73 MMR- deficient : 1782

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Single nucleotide variants introduce neo-epitopes Sahin et al, Current opinion immunology, 2016

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Mutant-antigen repertoire in human cancers Alexandrov et al,Nature 2013

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 EC – Four moleculair subtypes POLE MSI Copy number low Copy number high (ultra-mutated) (hyper-mutated) (endometrioid) (serous-like) Kandoth et al., Nature 2013

Gynecologic Cancer InterGroup Translational Research Brainstorming October 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 InterGroup Translational Research Brainstorming October 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 InterGroup Translational Research Brainstorming October 2016 Hypothesis

Gynecologic Cancer InterGroup Translational Research Brainstorming October 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 Van Gool, CCR 2015 25

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Increased density of intratumoral CD8+ lymphocytes in POLE mutants Van Gool and Eggink et al , CCR 2015 26

Gynecologic Cancer InterGroup Translational Research Brainstorming October 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 InterGroup Translational Research Brainstorming October 2016 Treatment selection based on immune resistance Hot tumors Cold tumors Ribas et al

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Antigens for vaccine development Neo antigens • 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

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Mellman, Immunity, 2013

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Melero et al, Nature Reviews Cancer 2015

Gynecologic Cancer InterGroup Translational Research Brainstorming When I said I, I meant we. When I said we, I meant them: October 2016 UMCG, Dept. of Gyn. Oncology LUMC, NL Thaline Prins Henriette Arts Tjalling Bosse Anouk Terwindt Refika Yigit Mariette van Poelgeest Fenne Komdeur Maaike Oonk Vincent Smit Florine Eggink Marian Mourits Carien Creutzberg Marco Versluis Ate van der Zee Sjoerd van der Burg Kim Brunekreeft Stephanie van de Wall Harry G. Klip ENITEC consortium, ESGO Hagma Workel Annechien Plat Joyce TRANSPORTEC consortium position for PhD student (MD) University of Southampton, UK Marco de Bruyn Bea Wisman Tim Elliott Valerie Wiersma University of Würzburg, Germany UMCG, Dept. of Pathology Harald Wajant Harry Hollema & Evelien Duiker University of Exeter, UK UMCG, Dept. of Genetics Paul Eggleton Pieter van de Vlies & Kim de Lange UMCG, Dept. of Virology University of Oxford, UK Toos Daemen David Church UMCG, Dept. of Hematology Aduro Edwin Bremer Andrea v. Elsas & Hans v. Eenenaam UMCG, Dept. of Med. Oncology TRON & GANYMED Steven de Jong & Marcel van Vught An Reyners & Hilde Jalving Ugur Sahin & Ozlem Türeci

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016