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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.

发展CAR - T细胞疗法靶向晚期前列腺癌的肿瘤异质性