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Project

Deciphering the neoantigen landscape in bladder cancer patients

Funder: Swiss National Science Foundation

Funding period
CHF 629 K
USD 643 K
Funding amount
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.

 
532
Projects
USD 285.8 M
Aggregated funding amount
USD 713 K
Average funding amount
Project list item
Epigenetic regulators of subtype plasticity in bladder cancer

Bladder Cancer Advocacy Network to John Robert Christin

USD 1,700
2020 - 2020
Project list item
Defining NRF2 induced tumor invasion in bladder cancer

Bladder Cancer Advocacy Network to Yuki Kita, William Youngkwan Kim, Bernard Weissman

USD 50,000
2020 - 2021
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Targeting regulatory B cells (Bregs) to improve anti-bladder cancer immunity

Bladder Cancer Advocacy Network to Burles Avner Johnson, David McConkey

USD 50,000
2020 - 2021
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Implication of neutrophil extracellular traps in the efficacy of bladder-sparing therapy in muscle invasive bladder cancer

Canadian Institutes of Health Research to Wassim Kassouf, Jonathan David Spicer, Ciriaco A. Piccirillo

USD 138,878
2020 - 2025
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Dissecting myeloid cell-mediated resistance to immune checkpoint blockade in bladder cancer

National Cancer Institute to NINA BHARDWAJ, JUN ZHU, MATTHEW GALSKY

USD 703,400
2020 - 2025
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CD40 agonism for the treatment of bladder cancer

National Cancer Institute to CHRISTOPHER STUART GARRIS

USD 64,554
2020 - 2023
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Effect of APOBEC3 on Bladder Cancer Biology and Response to Immunotherapy

National Cancer Institute to ANDREW TRUONG

USD 45,016
2020 - 2023
Project list item
A new bladder cancer model based on tissue reprogramming and gene targeting

National Cancer Institute to FLAMINIA TALOS, DAIFENG WANG

USD 203,843
2020 - 2021
Project list item
Analysis of the antineoplastic action of Class I HDAC inhibitors to define new combination therapies for urothelial carcinoma

German Research Foundation to Günter Niegisch, Michèle Janine Hoffmann

 
2020 -
Project list item
Roles of epigenetic regulators in bladder cancer progression

University of California - Cancer Research Coordinating Committee to Zhu Wang

USD 74,960
2020 - 2020
Project list item
Chemotherapy plus PD-1 blockade as bladder-sparing treatment for muscle-invasive bladder cancer

V Foundation for Cancer Research to Matthew D Galsky

USD 600,000
2019 - 2022
Project list item
Unravelling Mechanisms of Resistance to Checkpoint Inhibition in Canine Urothelial Carcinoma

V Foundation for Cancer Research to Nicola J. Mason

USD 500,000
2019 - 2021
Project list item
Engineering Smart Solutions for Disorders of the Bladder Urothelium

Engineering and Physical Sciences Research Council

 
2019 - 2023
Project list item
Bladder cancer chemotherapy potentiation with a multiprong arachidonic acid pathway modulator

National Cancer Institute to PAUL THOMAS HENDERSON

USD 300,000
2019 - 2020
Project list item
[The association between SORL1 and advanced bladder cancer] - Original in Japanese

Japan Society for the Promotion of Science to Takanobu UTSUMI

USD 26,335
2019 - 2021
Project list item
Geriatric Conditions and Treatment Burden in Older Adults with Non-Muscle-Invasive Bladder Cancer and Their Caregivers

National Institute on Aging to TULLIKA GARG

USD 271,698
2019 - 2021
Project list item
Developing a SMART scaffold for bladder augmentation

National Institute of Biomedical Imaging and Bioengineering to GUILLERMO ANTONIO AMEER, ARUN SHARMA, JOHN ROGERS

USD 1,399,891
2019 - 2023
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