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

项目总结 嵌合抗原受体(CAR)T细胞疗法是一种免疫疗法，已在临床上显示出成功 治疗血液系统恶性肿瘤，但在实体肿瘤的治疗中面临多重障碍，包括 免疫抑制肿瘤微环境(TME)阻碍免疫治疗的治疗反应 和异质性抗原表达，这降低了CAR T细胞的效力，这些细胞主要通过 针对抗原的特定靶点。使用合理设计的组合可以克服这两个挑战 允许更大程度地刺激先天免疫、T细胞渗透和CAR T细胞功效的治疗。我们的 该小组已经开发出针对前列腺中过度表达的前列腺干细胞抗原(PSCA)的CAR T细胞 目前正在进行一项治疗转移性阉割患者的第一阶段试验- 耐药前列腺癌(MCRPC)。为了在临床前模型中进一步研究这种疗法，我们开发了一种 以PSCA-CAR为靶点的小鼠前列腺癌免疫活性模型 小鼠T细胞。我们发现淋巴清除剂环磷酰胺对荷瘤小鼠有预适应作用 (Cy)有益地增强了TME，允许更多的内源性和CAR在肿瘤内的渗透 T细胞。然而，需要额外的修改以进一步改变TME并实现更耐用 回应。为此，已发现局部放射治疗(RT)可在很大程度上引起TME的变化 激活内源性免疫系统并通过T细胞触发抗肿瘤反应，促使研究 将焦点RT与其他基于免疫的策略相结合。令人费解的是，RT还能诱导几种免疫反应 抑制作用，这可能在限制治疗的抗原异种肿瘤模型中特别放大 T细胞效率。使用我们的临床前模型，我们计划开发和优化这种焦点RT和 PSCA-CAR T细胞来表征这些潜在的免费治疗策略。我们还计划 解开辐射对联合治疗的这些复杂影响，这将是最大限度地提高 CAR T细胞抗前列腺癌作用的研究目标1：我的目标是了解免疫调节剂是如何 焦点RT对TME和系统免疫的影响可能与CAR T细胞协同作用而产生高效 针对前列腺癌的治疗。目标2：我计划确定并克服对此的阻力机制 使用具有异质性抗原表达的前列腺癌的联合治疗。通过培训和 我的研究赞助人索尔·普里克曼博士提供的专业知识，他是为 实体肿瘤治疗，我的临床联合赞助人坦尼娅·多尔夫博士，负责我们第一阶段的临床研究员 试用，以及NCI指定的综合性癌症中心希望之城的研究生院，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.