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

项目 3：开发针对晚期前列腺癌肿瘤异质性的 CAR T 细胞疗法

基本信息

批准号：
10704575
负责人：
OWEN N. WITTE
金额：
$ 32.78万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10704575
关键词：
Address Androgen Receptor Antibodies Antigen Targeting Attention Binding Biological Models Biopsy Blood CAR T cell therapy Carcinoembryonic Antigen Cells Cities Clinical Trials Clonal Evolution Collaborations Collecting Cell Combined Modality Therapy Correlative Study Development Disease Disease Progression Disease Resistance Engineering Generations Genetic Engineering Glucocorticoid Receptor Heterogeneity Human Immune Immunooncology Immunotherapy Infusion procedures Knowledge Laboratories Life Malignant Neoplasms Malignant neoplasm of prostate Mediating Modeling Molecular Nature Neoplasm Circulating Cells Neoplasm Metastasis Neuroendocrine Prostate Cancer Normal tissue morphology Oncology PIK3CG gene Pathway interactions Patients Phase I Clinical Trials Phenotype Pre-Clinical Model Prostate Adenocarcinoma Prostate Cancer therapy Proteins Quality of life Receptor Signaling Research Resistance Safety Scientific Advances and Accomplishments Series Specificity Specimen Surface Surface Antigens T-Lymphocyte Technology Testing Therapeutic Toxic effect Tumor Escape Tumor Markers Tumor Tissue Variant Work advanced disease advanced prostate cancer androgen biosynthesis androgen deprivation therapy anti-tumor immune response anticancer treatment bone burden of illness cancer subtypes cancer therapy castration resistant prostate cancer chimeric antigen receptor chimeric antigen receptor T cells clinically relevant experience first-in-human genomic biomarker improved liquid biopsy men molecular marker mouse model neoplastic cell novel novel therapeutics palliative patient population predictive marker prostate cancer model prostate stem cell antigen resistance mechanism response safety and feasibility therapy resistant transdifferentiation treatment response tumor tumor DNA tumor heterogeneity tumor microenvironment

项目摘要

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.

开发汽车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疗法是治疗的主要手段晚期前列腺癌患者。但是，大多数男性最终会发展出抗性疾病称为耐Cantration-抗抑制前列腺癌（CRPC）。转移性CRPC无法治愈，在此阶段治疗旨在扩展和改善生活质量。 CRPC是一种至少由包括前列腺腺癌和神经内分泌前列腺癌（NEPC）的两种亚型。两个CRPC 亚型在许多致命的，耐药的前列腺中共同发现。新的和潜在的疗法迫切需要考虑并消除CRPC的异质性。嵌合抗原受体（CAR）T细胞疗法是肿瘤学的革命性进步，结合了精度靶向有效杀死肿瘤细胞。在这种方法中，患者自己的免疫T细胞是从中收集的血液通常设计为识别和杀死他/她的特定癌症并重新引入患者。该技术有可能改变癌症治疗的治疗无法治愈。我们的小组已将转移性CRPC转移到首次通过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）是蛋白质在大多数前列腺腺癌表面表达，开发了结合的抗体专门针对PSCA，并在实验室模型中进行了广泛设计和测试的PSCA CAR T细胞疗法前列腺癌。最近，我们还发现另一种蛋白质，癌症抗原相关细胞粘附分子5（CEACAM5）在大多数NEPC的表面表达。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细胞转移性CRPC，并询问患者标本，以阐明使用治疗耐药性的机制特别注意NEPC的出现。我们还将设计和评估针对安全的汽车并专门针对NEPC实验室模型中的CEACAM5。最后，我们将确定策略是否通过使用PSCA CAR T和CECAM5 CAR T细胞可以通过CRPC安全地解决肿瘤异质性消除前列腺腺癌和NEPC。