Project 3: Developing CAR T Cell Therapies to Target Tumor Heterogeneity in Advanced Prostate Cancer

开发CAR T细胞疗法以靶向晚期前列腺癌中的肿瘤异质性 抑制雄激素生物合成和靶向雄激素受体的疗法是治疗雄激素缺乏症的主要方法。 晚期前列腺癌患者。然而，大多数男性最终会患上耐药疾病， 称为去势抵抗性前列腺癌（CRPC）。转移性CRPC是不可治愈的，在这个阶段的治疗 旨在延长和提高生活质量。CRPC是一种异质性疾病，至少由 两种亚型包括前列腺癌和神经内分泌前列腺癌（NEPC）。两个CRPC 在许多致命的、治疗抵抗性前列腺癌中发现亚型。新的和有效的疗法， 因此，迫切需要解释和消除CRPC的异质性。 嵌合抗原受体（CAR）T细胞疗法是肿瘤学的一项革命性进展， 以强大的杀伤肿瘤细胞为目标。在这种方法中，患者自身的免疫T细胞被收集， 血液，基因工程识别和杀死他/她的特定癌症，并重新引入病人。 这项技术有可能改变癌症的治疗，包括那些已经被认为是 无法治愈我们的团队已经将第一种用于转移性CRPC的CAR T细胞疗法推向临床试验， 建立在一系列科学成就之上。我们发现前列腺干细胞抗原（PSCA）是一种 大多数前列腺癌细胞表面表达的蛋白质， 特别是PSCA，并在实验室模型中广泛工程化和测试PSCA CAR T细胞疗法。 前列腺癌最近，我们还发现另一种蛋白，癌胚抗原相关细胞， 粘附分子5（CEACAM 5）在大多数NEPC的表面上表达。 在拟议的研究中，我们将启动一项I期临床试验，以评估我们的PSCA CAR T细胞在患有 转移性CRPC，并询问患者标本，以阐明治疗耐药机制， 特别注意新环境保护委员会的出现。我们还将设计和评估汽车， 并在NEPC的实验室模型中特异性靶向CEACAM 5。最后，我们将确定一个战略是否 联合PSCA CAR T和CEACAM 5 CAR T细胞可以通过以下方式安全地解决CRPC中的肿瘤异质性： 根除前列腺腺癌和NEPC。

Developing CAR T Cell Therapies to Target Tumor Heterogeneity in Advanced Prostate Cancer Therapies that inhibit androgen biosynthesis and target the androgen receptor are the mainstay of treatment for patients with advanced prostate cancer. However, most men will eventually develop resistant disease that is called castration-resistant prostate cancer (CRPC). Metastatic CRPC is not curable and treatments at this stage are aimed at extending and improving quality of life. CRPC is a heterogeneous disease composed of at least two subtypes including prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC). Both CRPC subtypes are found together in many lethal, treatment-resistant prostate cancers. New and potent therapies that account for and eliminate the heterogeneity of CRPC are urgently needed. Chimeric antigen receptor (CAR) T cell therapy is a revolutionary advance in oncology that combines precision targeting with powerful killing of tumor cells. In this approach, a patient’s own immune T cells are collected from the blood, genetically engineered to recognize and kill his/her specific cancer and reintroduced into the patient. This technology has the potential to transform the treatment of cancer including those that have been considered incurable. Our group has pushed forward the first CAR T cell therapy for metastatic CRPC to a clinical trial by building on a series of scientific accomplishments. We discovered that prostate stem cell antigen (PSCA) is a protein expressed on the surface of the majority of prostate adenocarcinomas, developed antibodies that bind specifically to PSCA, and extensively engineered and tested PSCA CAR T cell therapy in laboratory models of prostate cancer. Recently, we have also found that another protein, carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5), is expressed on the surface of most NEPCs. In the proposed research, we will initiate a phase I clinical trial to evaluate our PSCA CAR T cells in patients with metastatic CRPC, and interrogate patient specimens to elucidate mechanisms of treatment resistance with particular attention given to the emergence of NEPC. We will also engineer and evaluate CARs aimed at safely and specifically targeting CEACAM5 in laboratory models of NEPC. Lastly, we will determine whether a strategy combining PSCA CAR T and CEACAM5 CAR T cells can safely address tumor heterogeneity in CRPC by eradicating both prostate adenocarcinoma and NEPC.