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

发展CAR T细胞疗法以靶向晚期前列腺癌的肿瘤异质性 抑制雄激素生物合成和靶向雄激素受体的治疗是治疗慢性前列腺癌的主要方法 晚期前列腺癌患者。然而，大多数男性最终会患上抗药性疾病，即 称为耐阉割前列腺癌(CRPC)。转移性的CRPC是不可治愈的，现阶段的治疗 旨在延长和提高生活质量。慢性前列腺癌是一种异质性疾病，至少由 前列腺癌和神经内分泌性前列腺癌(NEPC)两种亚型。两个CRPC 在许多致命的、耐药的前列腺癌中，亚型一起被发现。新的有效疗法 说明和消除CRPC的异质性是当务之急。 嵌合抗原受体(CAR)T细胞疗法是肿瘤学中的革命性进展，它结合了精确度 靶向对肿瘤细胞具有强大的杀伤力。在这种方法中，患者自己的免疫T细胞从 这种血液经过基因工程改造，可以识别和杀死他/她特定的癌症，并重新注入患者体内。 这项技术有可能改变癌症的治疗，包括那些已经被考虑的癌症的治疗 不治之症。我们小组已经将第一个治疗转移性CRPC的CAR T细胞疗法推向临床试验， 建立在一系列科学成就的基础上。我们发现前列腺干细胞抗原(PSCA)是一个 大多数前列腺癌表面表达的蛋白质，产生了结合抗体 特别针对PSCA，并在实验室模型中广泛设计和测试PSCA CAR T细胞疗法 前列腺癌。最近，我们还发现了另一种蛋白质，癌胚抗原相关细胞 黏附分子5(CEACAM5)，表达于大多数NEPC的表面。 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 转移的CRPC，并询问患者样本以阐明治疗耐药的机制 特别注意国家石油公司的出现。我们还将设计和评估旨在安全的汽车 并在NEPC的实验室模型中特异性靶向CEACAM5。最后，我们将确定一个战略是否 联合PSCA CAR T和CEACAM5 CAR T细胞可通过以下方式安全地处理CRPC中的肿瘤异质性 根除前列腺癌和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.