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RP-4: Immunologic Predictors of BCG Immunotherapy for Bladder Cancer

RP-4：膀胱癌 BCG 免疫治疗的免疫预测因子

基本信息

批准号：
10226974
负责人：
Michael Stephen Glickman
金额：
$ 35.13万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-24 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226974
关键词：
Antigens Area Attenuated BCG Live Bacillus Calmette-Guerin Therapy Bacterial Attachment Site Basic Science Bladder Bladder Neoplasm CD8-Positive T-Lymphocytes Clinical Clinical Sciences Clinical Trials Cytolysis Data Diagnosis Excision Genetic Screening Human Immune Immune response Immunity Immunologics Impairment Inflammation Inflammatory Inflammatory Response Intervention Investigation Malignant neoplasm of urinary bladder Mediating Methods Modeling Morbidity - disease rate Mus Mutation Mycobacterium bovis Outcome Patient-Focused Outcomes Patients Phase Radical Cystectomy Reaction Recurrence Resistance Risk T cell response T cell therapy T-Lymphocyte Testing Treatment Efficacy Tumor Antigens Tumor Immunity Urothelium Vaccination base bladder transitional cell carcinoma cancer cell chemotherapy clinical candidate improved individual patient intravesical mortality mouse model mutant mycobacterial neoantigens neoplastic cell non-muscle invasive bladder cancer standard of care subcutaneous tool treatment choice treatment response tumor

项目摘要

PROJECT SUMMARY/ABSTRACT The standard of care for most patients with non-muscle-invasive bladder cancer (NMIBC) is cystoscopic resection followed by intravesical therapy with bacillus Calmette-Guérin (BCG). Outcomes for patients treated with BCG are comparable to those of patients treated with radical cystectomy, and are superior to intravesical chemotherapy; however, there is still a substantial risk of recurrence of bladder cancer among BCG-treated patients. Currently, there are no reliable methods to predict an individual patient's outcome. The mechanism of action of BCG therapy for bladder cancer remains an area of active investigation. Using the MB49 orthotopic mouse model of BCG therapy, we have compiled data demonstrating that BCG elicits an immune response to tumor-specific antigens. Mice cured of MB49 bladder cancer by BCG therapy were specifically resistant to a subsequent challenge with subcutaneous MB49 tumors. This resistance was not seen in mice that received intravesical BCG therapy in the absence of a bladder tumor. Furthermore, adoptive transfer of T-cells from mice surviving MB49 bladder cancer after BCG therapy conferred a survival advantage to naïve mice instilled with intravesical MB49, but there was no advantage using T-cells from mice who received intravesical BCG therapy in the absence of a bladder tumor. These results strongly suggest that an initial inflammatory reaction invoked by BCG results in T-cell-dependent tumor immunity and put forward the possibility that interventions to enhance tumor-specific immunity should enhance BCG efficacy. Based on these data, we propose a model of BCG efficacy with the following components: A) The first phase of BCG therapy involves engulfment of BCG by tumor cells, leading to local inflammation and immune-mediated tumor cell lysis. B) Tumor cell lysis in the context of BCG-induced inflammation primes a T-cell-dependent, neoantigen-directed immune response that results in elimination of tumor cells in the bladder and subsequent tumor immunity. We will test the hypotheses generated by this model to identify strategies to enhance the efficacy of BCG therapy by: 1) testing BCG strains with enhanced capacity to infect bladder tumor cells, enhanced or impaired survival within bladder cancer cells, or enhanced ability to induce an inflammatory response in a mouse model of bladder cancer; 2) determining the magnitude and diversity of the BCG-induced tumor neoepitope-specific T-cell response and testing whether neoepitope vaccination can enhance BCG-induced tumor elimination in a mouse model of bladder cancer. We will also attempt to develop a clinically useful tool to predict an individual patient's likelihood of therapeutic response to BCG therapy by determining whether mutational or neoantigen load predict the therapeutic efficacy of BCG in human patients with NMIBC.

项目总结/文摘