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: 10453636
• 负责人: Michael Stephen Glickman
• 金额: $ 34.33万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453636
• 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 大多数非肌肉侵入性膀胱癌（NMIBC）患者的护理标准是膀胱镜 切除术，然后进行静脉治疗，并用状态杆菌Calmette-guérin（BCG）进行切除。治疗患者的结果 与BCG相比，接受了从根治性膀胱切除术治疗的患者的患者相当，并且优于静脉内 化学疗法；但是，在经BCG治疗中，仍存在膀胱癌复发的巨大风险 患者。当前，没有可靠的方法可以预测患者的结果。机制 BCG治疗对膀胱癌的作用仍然是一个积极研究的领域。使用MB49原位 BCG治疗的小鼠模型，我们已经编译了数据，表明BCG对 肿瘤特异性抗原。通过BCG治疗治疗MB49膀胱癌的小鼠特异性抗药性 随后对皮下MB49肿瘤的挑战。在收到的小鼠中看不到这种抗药性 在没有膀胱肿瘤的情况下，静脉内BCG治疗。此外，T细胞的自适应转移 BCG治疗后幸存的MB49膀胱癌的小鼠赋予了幼稚小鼠的生存优势 使用静脉内MB49，但是使用接受静脉内BCG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。这些结果强烈表明初始炎症反应 由BCG调用会导致T细胞依赖性肿瘤免疫，并提出了干预措施的可能性 增强肿瘤特异性免疫应提高BCG效率。基于这些数据，我们提出了一个模型 BCG效率具有以下组件：a）BCG治疗的第一阶段涉及BCG吞噬BCG 肿瘤细胞，导致局部炎症和免疫介导的肿瘤细胞裂解。 b）肿瘤细胞裂解 BCG诱导的炎症的背景是T细胞依赖性的，新抗原指导的免疫反应 导致消除膀胱中的肿瘤细胞和随后的肿瘤免疫力。我们将测试假设 该模型生成以确定提高BCG治疗效率的策略：1）测试BCG 具有增强感染膀胱肿瘤细胞能力增强的菌株，在膀胱内增强或受损的生存率 癌细胞，或增强在膀胱癌小鼠模型中诱导炎症反应的能力； 2） 确定BCG诱导的肿瘤新EPITOPE特异性T细胞反应的大小和多样性和 测试新血统疫苗是否可以在小鼠模型中增强BCG诱导的肿瘤消除 膀胱癌。我们还将尝试开发一种临床上有用的工具来预测个体患者的 通过确定突变和新抗原负荷是对BCG治疗的治疗反应的可能性 预测BCG在NMIBC患者患者中的治疗效率。