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

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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

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Overview of immune aspects

  • endometrial / cervical cancer-

Hans Nijman Lisban GCIG meeting, Thursday October 27th, 2016

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Mellman, Immunity, 2013

Immune response against cancer

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Tumor Infiltrating T cells

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Treatment selection based on immune resistance

Ribas et al

Hot tumors Cold tumors

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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CD8+ cells CD103+ cells

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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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

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9 Komdeur&Wouters et al. Oncotarget. In print.

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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10 Komdeur&Wouters et al. Oncotarget. In print.

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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11 Komdeur&Wouters et al. Oncotarget. In print.

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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12 Komdeur&Wouters et al. Oncotarget. In print.

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Treatment selection based on immune resistance

Ribas et al

Hot tumors Cold tumors

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Releasing the breakes on Cancer Immunotherapy

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Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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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

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Le et al, NEJM 2015 Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Pembrolizumab in tumors with mismatch-repair deficiency

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Le et al, NEJM 2015 Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Pembrolizumab in tumors with mismatch-repair deficiency

Objective RR MMR-deficient Colorectal 4/10 (40%) MMR-proficient Colorectal 0/18 ( 0%) MMR-deficient Non-colorectal 5/7 (71%)

  • 2 casus of EC: 1 CR & 1 PR

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Le et al, NEJM 2015 Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Mean somatic mutations per tumor

(whole exome sequencing)

MMR- proficient: 73 MMR- deficient : 1782

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Single nucleotide variants introduce neo-epitopes

Sahin et al, Current opinion immunology, 2016 Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Mutant-antigen repertoire in human cancers

Alexandrov et al,Nature 2013 Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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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 InterGroup Translational Research Brainstorming October 2016

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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

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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

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Hypothesis

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Do POLE mutant endometrial cancers show increased immunogenicity?

  • Analysis of immune infiltration in 150 tumor samples from

PORTEC 1 and 2, LUMC and UMCG

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Van Gool, CCR 2015

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Increased density of intratumoral CD8+ lymphocytes in POLE mutants

Van Gool and Eggink et al , CCR 2015

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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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

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Treatment selection based on immune resistance

Ribas et al

Hot tumors Cold tumors

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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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

  • ut 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 InterGroup Translational Research Brainstorming October 2016

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

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Melero et al, Nature Reviews Cancer 2015

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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UMCG, Dept. of Gyn. Oncology

Thaline Prins Henriette Arts Anouk Terwindt Refika Yigit Fenne Komdeur Maaike Oonk Florine Eggink Marian Mourits Marco Versluis Ate van der Zee Kim Brunekreeft Stephanie van de Wall Harry G. Klip Hagma Workel Annechien Plat Joyce position for PhD student (MD) Bea Wisman

Marco de Bruyn

Valerie Wiersma

UMCG, Dept. of Hematology

Edwin Bremer

University of Würzburg, Germany

Harald Wajant

University of Exeter, UK

Paul Eggleton

When I said I, I meant we. When I said we, I meant them:

UMCG, Dept. of Virology

Toos Daemen

UMCG, Dept. of Med. Oncology

Steven de Jong & Marcel van Vught An Reyners & Hilde Jalving

University of Southampton, UK

Tim Elliott

LUMC, NL

Tjalling Bosse Mariette van Poelgeest Vincent Smit Carien Creutzberg Sjoerd 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 Pathology

Harry Hollema & Evelien Duiker

UMCG, Dept. of Genetics

Pieter van de Vlies & Kim de Lange Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016

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Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016