Designing Rational Combinations to Improve CAR T Cell Therapy for Prostate Cancer

项目摘要 嵌合抗原受体（CAR）T细胞疗法是一种免疫疗法，已在临床上取得成功， 但在实体瘤的治疗中面临多重障碍，包括 免疫抑制性肿瘤微环境（TME）阻碍对免疫疗法的治疗反应 和异质性抗原表达，这降低了CAR T细胞的功效，CAR T细胞主要通过 抗原的特异性靶向。这两个挑战都可以通过合理设计的组合来克服 允许更大刺激先天免疫、T细胞浸润和CAR T细胞功效的疗法。我们 研究小组已经开发出针对前列腺中过表达的前列腺干细胞抗原（PSCA）的CAR T细胞， 癌症，目前正在进行的1期试验中测试它们，以治疗转移性去势患者- 耐药前列腺癌（mCRPC）。为了进一步研究临床前模型中的治疗，我们开发了一种 使用PSCA-CAR工程化靶向的小鼠前列腺肿瘤的免疫活性小鼠模型 小鼠T细胞。我们发现用淋巴细胞清除剂环磷酰胺预处理荷瘤小鼠， (Cy)有利地增强了TME，允许内源性和CAR的更大的肿瘤内浸润 T细胞。然而，需要额外的修改以进一步改变TME并实现更持久的 应答为此，已经发现局灶性放疗（RT）诱导TME的变化， 激活内源性免疫系统并通过T细胞引发抗肿瘤反应，促使研究 将联合收割机局灶性RT与其他基于免疫的策略相结合。令人困惑的是，RT也已知诱导几种免疫反应。 抑制作用，这可能在限制CAR的抗原异质性肿瘤模型中特别放大 T细胞功效使用我们的临床前模型，我们计划开发和优化这种局灶性RT与 PSCA-CAR T细胞来表征这些潜在的互补治疗策略。我们还计划 解开这些复杂的影响，辐射的联合治疗，这将是至关重要的最大限度地提高 CAR T细胞对前列腺癌的抗肿瘤作用。目的1：我的目的是了解免疫调节 局灶性RT对TME和全身免疫的作用可能与CAR T细胞协同作用， 治疗前列腺肿瘤。目标2：我计划识别并克服对此的耐药机制 使用具有异质抗原表达的前列腺肿瘤的联合疗法。与训练和 我的研究赞助商扫罗·普莱斯曼博士提供了专业知识，他是开发CAR T细胞疗法的专家， 实体瘤治疗，我的临床共同申办者Tanya Dorff博士，负责我们1期研究的临床研究者 试验，和研究生院在希望之城，一个国家癌症研究所指定的综合癌症中心，我将能够 实现这些目标中提出的F31博士前奖学金申请。

PROJECT SUMMARY Chimeric antigen receptor (CAR) T cell therapy is a type of immunotherapy that has shown clinical success in treating hematological malignancies but faces multiple barriers in the treatment of solid tumors, including an immunosuppressive tumor microenvironment (TME) that hampers therapeutic responses to immunotherapies and heterogeneous antigen expression, which reduces the efficacy of CAR T cells that function primarily through specific targeting of an antigen. Both challenges may be overcome using rationally designed combination therapies that allow for greater stimulation of innate immunity, T cell infiltration, and CAR T cell efficacy. Our group has developed CAR T cells targeting the prostate stem cell antigen (PSCA) overexpressed in prostate cancer and is currently testing them in an ongoing phase 1 trial to treat patients with metastatic castration- resistant prostate cancer (mCRPC). To further examine the therapy in preclinical models, we developed an immunocompetent mouse model using mouse prostate tumors that are targeted with PSCA-CAR engineered mouse T cells. We found that preconditioning tumor-bearing mice with lymphodepleting agent cyclophosphamide (Cy) beneficially enhanced the TME, allowing for greater intra-tumoral infiltration of both endogenous and CAR T cells. However, additional modifications are needed to further alter the TME and achieve more durable responses. To this end, focal radiotherapy (RT) has been found to induce changes in the TME that largely activate the endogenous immune system and trigger anti-tumor responses by T cells, prompting studies to combine focal RT with other immune-based strategies. Perplexingly, RT is also known to induce several immune suppressive effects, which may be particularly magnified in antigen-heterogenous tumor models that limit CAR T cell efficacy. Using our preclinical model, we plan to develop and optimize this combination of focal RT with PSCA-CAR T cells to characterize these potentially complimentary therapeutic strategies. We also plan to unravel these complex effects of radiation on the combination therapy, which will be essential for maximizing the anti-tumor effects of CAR T cells against prostate cancer. Aim 1: I aim to understand how the immunomodulatory effects of focal RT on the TME and systemic immunity may synergize with CAR T cells to develop highly effective treatments against prostate tumors. Aim 2: I plan to identify and overcome resistance mechanisms against this combination therapy using prostate tumors with heterogeneous antigen expression. With the training and expertise provided by my research sponsor Dr. Saul Priceman, an expert in developing CAR T cell therapies for solid tumor treatment, my clinical co-sponsor Dr. Tanya Dorff, the clinical investigator in charge of our phase 1 trial, and the graduate school at City of Hope, an NCI-designated comprehensive cancer center, I will be able to achieve these goals set forth in this F31 Predoctoral Fellowship application.