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

• 批准号: 9979823
• 负责人: Michael Stephen Glickman
• 金额: $ 35.64万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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/9979823
• 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

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.

项目摘要/摘要 大多数非肌肉浸润性膀胱癌(NMIBC)患者的标准治疗是膀胱镜检查。 切除后用卡介苗(BCG)进行膀胱内治疗。接受治疗的患者的结果 卡介苗与根治性膀胱切除术的疗效相当，优于膀胱腔内注射。 化疗；然而，在接受卡介苗治疗的人中，膀胱癌复发的风险仍然很大 病人。目前，还没有可靠的方法来预测单个患者的预后。它的作用机制 卡介苗治疗膀胱癌的作用仍是一个积极研究的领域。使用MB49正位机 卡介苗治疗的小鼠模型，我们汇编的数据表明卡介苗引起免疫反应 肿瘤特异性抗原。卡介苗治疗治愈的MB49膀胱癌小鼠对A 随后挑战皮下MB49肿瘤。这种抵抗力在接受注射的小鼠身上没有看到 无膀胱肿瘤的膀胱内卡介苗治疗。此外，T细胞的过继转移 卡介苗治疗后在MB49膀胱癌中存活的小鼠对灌输的幼稚小鼠具有生存优势 使用膀胱内注射MB49，但使用来自膀胱内注射卡介苗的小鼠的T细胞没有优势 在没有膀胱肿瘤的情况下进行治疗。这些结果强烈地表明，最初的炎症反应 由卡介苗引起的T细胞依赖的肿瘤免疫，并提出了干预的可能性 增强肿瘤特异性免疫应增强卡介苗疗效。基于这些数据，我们提出了一个模型 卡介苗疗效：a)卡介苗治疗的第一阶段包括通过以下方式吞噬卡介苗 肿瘤细胞，导致局部炎症和免疫介导的肿瘤细胞溶解。B)肿瘤细胞裂解 卡介苗诱导的炎症启动T细胞依赖的新抗原导向的免疫反应 结果消除了膀胱中的肿瘤细胞和随后的肿瘤免疫。我们将检验这些假设 由该模型生成，通过以下方式确定提高卡介苗治疗效果的策略：1)检测卡介苗 感染膀胱肿瘤细胞的能力增强、膀胱内生存能力增强或受损的菌株 癌细胞，或在膀胱癌小鼠模型中诱导炎症反应的增强能力；2) 测定卡介苗诱导的肿瘤新表位特异性T细胞反应的大小和多样性 检测新表位疫苗能否增强卡介苗诱导的小鼠肿瘤清除 膀胱癌。我们还将尝试开发一种临床上有用的工具来预测单个患者的 通过确定突变或新的抗原负载来确定卡介苗治疗反应的可能性 预测卡介苗治疗人类NMIBC的疗效。