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Deciphering the neoantigen landscape in bladder cancer patients

English title Deciphering the neoantigen landscape in bladder cancer patients
Applicant Derré Laurent
Number 175559
Funding scheme Project funding (Div. I-III)
Research institution Service d'Urologie CHUV
Institution of higher education University of Lausanne - LA
Main discipline Immunology, Immunopathology
Start/End 01.03.2018 - 28.02.2022
Approved amount 628'644.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Experimental Cancer Research

Keywords (5)

neoantigens; mutanome; immunotherapy; bladder cancer; BCG

Lay Summary (French)

Lead
Caractérisation des néoantigènes dans le cancer de la vessieLeadL’immunothérapie est une thérapie prometteuse contre le cancer, puisqu’elle cible le système immunitaire plutôt que la tumeur et permet l’établissement d’une mémoire immunitaire. Cependant, un des obstacles majeurs à l’élimination d’un cancer par immunothérapie est la capacité du cancer à activer différents mécanismes inhibant le système immunitaire, ainsi que le manque d’antigène spécifiques de la tumeur. Les mutations génétiques spécifiques des tumeurs représentent des cibles idéales pour l’immunothérapie. En effet, les antigènes issus de ces mutations sont spécifiques de la tumeur et peuvent être perçus par le système immunitaire comme des antigènes étrangers (néoantigènes).
Lay summary

Contenu et objectif du travail de recherche
Le cancer de la vessie est un important problème de santé publique à cause de sa prévalence et de son fort taux de récidive. Le traitement standard du cancer de la vessie non-musculo-invasif consiste en l’instillation dans la vessie du Bacille de Calmette et Guérin (BCG), après résection de la tumeur. Cependant, 30 à 40% des patients ont une intolérance ou une résistance à ce traitement, limitant son utilisation et soulignant la nécessité de traitement alternatif ou complémentaire.
Notre principal objectif est d’analyser la présence, la quantité et l’antigénicité des néoantigènes chez les patients atteints de cancer musculo et non-musculo-invasif de la vessie (MIBC et NMIBC).
Plus précisément, nous souhaitons séquencer les tumeurs de patients, afin de caractériser l’expression des néoantigènes. Puis, nous étudierons si les cellules T sanguines ou issues de la tumeur peuvent être reconnaître et être activé par les néoantigènes identifiés. Finalement, nous caractériserons les capacités fonctionnelles des cellules T spécifiques de néoantigènes.

Contexte scientifique et social du projet de recherche
Notre étude est principalement destinée à répondre à la question de savoir si les néoantigènes exprimés par les tumeurs de la vessie peuvent être des cibles pour l’immunothérapie de ce cancer. Ce travail générera des informations permettant de développer de nouveaux traitements personnalisés contre le cancer de la vessie.
Direct link to Lay Summary Last update: 11.01.2018

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
183398 Deep interrogation of cancer immunotherapy 01.03.2019 R'EQUIP

Abstract

Immunotherapy has long been recognized as a promising therapy to fight cancer due to its specificity, its long term effects towing to immunological memory and its targeting of the immune system rather than of the tumor itself. However, control of tumor growth by immunotherapy is hindered by a number of obstacles including the activation of various immunosuppressive mechanisms and the lack of specific tumor antigen, which can strongly activate anti-tumor T cells. Immunotherapy of cancer has gained wide recognition in recent years with the characterization of immune checkpoints involved in the dampening of effective tumor antigen-specific T cell functions. The targeting of these immune checkpoints led to significant and impressive clinical successes. In addition, cancer mutations theoretically represent ideal targets for cancer immunotherapy as they combine a favorable safety due to the lack of their expression in healthy tissues and their capability of high immunogenicity as they are not affected by central tolerance mechanisms. Although, neoantigens are mostly patient-specific, recent advances in next-generation sequencing and computational prediction allowed the rapid and affordable characterization of genetic alterations in tumor and the identification of resulting neoepitopes, paving the road to patient-tailored immunotherapy. Moreover, several studies highlighted that neoepitope-specific T cells may be a key player in the efficacy of immune checkpoint blockade. More investigations are thus needed to understand whether mutational burden, presence of neoepitope-specific T cells and immune checkpoint expression are linked to cancer clinical outcome, particularly in bladder cancer.Bladder cancer remains a public health concern due to its prevalence, high risk of recurrence and associated cost of management. Although Bacillus Calmette-Guérin (BCG) instillations for urothelial cancer therapy is the most successful immunotherapy on a large scale and considered as a standard treatment for this indication, repeated BCG treatments are associated with significant toxicity and failure, underlying the necessity for alternative or complementary immunotherapy and for better understanding of T cell responses generated within bladder mucosa. Thus, the aim of this grant proposal is two-fold:1 - Evaluate in bladder cancer patients the spontaneous and treatment-mediated anti-neoantigen CD8+ T cell repertoire.2 - Comprehensively characterize the expression profile of immune checkpoints by CD8+ neoepitope-specific T cells.Experimental design and methods: Sequencing of non-muscle invasive (NMIBC) and muscle invasive bladder cancer tumors followed by bioinformatics analysis will be performed in order to establish putative neoepitopes. Pool of peptides will be then screened for recognition by autologous peripheral mononuclear cells (PBMC) and tumor infiltrating lymphocytes (TIL), but also by T cells isolated from urine of NMIBC patients undergoing BCG treatment. Specificity and class-I HLA restriction will be confirmed by neoepitope peptide-MHC multimer complex labeling. Finally, functional characterization (cytokine secretion, proliferation and cytotoxicity) and V repertoire analysis will be performed. In parallel, we will analyze in-depth the expression pattern of 37 immune checkpoint inhibitors by neoepitope-specific T cells using Chipcytometry in PBMC and frozen section of bladder tumors.Overall, we believe that in depth study of neoantigen-specific T cells and immune checkpoints will provide valuable clues to the development of new therapeutic strategies for bladder cancer patients.
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