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.

项目总结/摘要 大多数非肌层浸润性膀胱癌（NMIBC）患者的标准治疗是膀胱镜检查 切除后膀胱内灌注卡介苗（BCG）治疗。治疗患者的结局 BCG膀胱灌注组与根治性膀胱灌注组的疗效相当，且优于膀胱灌注组（上级 膀胱癌复发的风险很大，但是，膀胱癌复发的风险也很大。 患者目前，还没有可靠的方法来预测个体患者的结果。的机理 BCG治疗膀胱癌的作用仍然是一个积极研究的领域。使用MB 49 orthotopic 在BCG治疗的小鼠模型中，我们收集的数据表明BCG增强了对 肿瘤特异性抗原。通过BCG治疗治愈的MB 49膀胱癌小鼠特异性地对一种 随后用皮下MB 49肿瘤攻击。这种抵抗力在接受了 在没有膀胱肿瘤的情况下进行膀胱内BCG治疗。此外，T细胞的过继转移来自 BCG治疗后存活的MB 49膀胱癌小鼠赋予了滴注BCG的幼稚小鼠生存优势。 膀胱内注射MB 49，但使用接受膀胱内注射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。这些结果有力地表明，最初的炎症反应 BCG引起的T细胞依赖性肿瘤免疫的结果，并提出了干预措施， 增强肿瘤特异性免疫应增强卡介苗的疗效。基于这些数据，我们提出了一个模型， A）BCG治疗的第一阶段涉及BCG被以下组分吞噬： 肿瘤细胞，导致局部炎症和免疫介导的肿瘤细胞溶解。B）肿瘤细胞溶解， BCG诱导的炎症引发T细胞依赖性、新抗原导向的免疫应答， 导致膀胱中肿瘤细胞的消除和随后的肿瘤免疫。我们将检验 通过该模型产生的，以确定通过以下方式增强BCG治疗功效的策略：1）测试BCG 具有增强的感染膀胱肿瘤细胞的能力，增强或削弱膀胱内存活的菌株 癌细胞，或在膀胱癌小鼠模型中诱导炎症反应的能力增强; 2） 确定BCG诱导的肿瘤新表位特异性T细胞应答的幅度和多样性， 测试新表位疫苗接种是否可以增强BCG诱导的小鼠模型中的肿瘤消除。 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 通过确定突变或新抗原载量， 预测BCG在患有NMIBC的人类患者中的治疗效果。