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Targeting Cancer-Associated Fibroblasts Prevents Resistance to Chimeric Antigen Receptor T Cell Therapy

靶向癌症相关成纤维细胞可预防嵌合抗原受体 T 细胞疗法的耐药性

基本信息

批准号：
10506027
负责人：
Reona Sakemura
金额：
$ 17.12万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10506027
关键词：
Antigen Targeting Antigens Apoptosis B lymphoid malignancy B-Lymphocytes Bioinformatics Bone Marrow CAR T cell therapy CD34 gene Cancer Biology Cell Line Cell Maturation Cell physiology Cell surface Cells Cellular immunotherapy Clinic Clinical Trials Coculture Techniques Complex Data Development Disease remission Exposure to Fibroblasts Flow Cytometry Functional disorder Funding Future Goals Hematopoietic stem cells Immune Immunology Immunotherapeutic agent Immunotherapy Infusion procedures Luciferases Malignant - descriptor Malignant Neoplasms Mentors Modeling Molecular Biology Multiple Myeloma Outcome PD-1/PD-L1 Patients Plasma Cells Pre-Clinical Model Prevention Refractory Relapse Research Research Activity Resistance Safety Sampling Scientist Serious Adverse Event Site Solid Solid Neoplasm T-Lymphocyte Technical Expertise Techniques Testing Toxic effect Training Transforming Growth Factor beta Treatment Failure base cancer cell cancer immunotherapy cancer type career chemokine chimeric antigen receptor chimeric antigen receptor T cells clinically relevant curative treatments cytokine design experience fibroblast-activating factor high throughput screening humanized mouse improved innovation mouse model neoplastic cell novel novel strategies peripheral blood prevent programmed cell death ligand 1 programmed cell death protein 1 receptor resistance mechanism response safety study trafficking translational medicine translational scientist treatment strategy tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT A major breakthrough in cancer immunotherapy in the last decade is the development of chimeric antigen receptor (CAR) T cell therapy. Although anti-B cell maturation antigen (BCMA) directed CART cell therapy demonstrated unprecedented initial responses in patients with relapse/refractory B-cell malignancies or multiple myeloma (MM), respectively, durable responses are limited. The mechanisms of relapse after CART cell therapy are not fully unveiled yet. The long-term goal of my proposal is to uncover mechanisms of resistance to CART cell therapy and to develop an independent research career focused on targeting the tumor microenvironment simultaneously with CART cells. The unifying objective of this application is to design novel strategies for the treatment and prevention of tumor immunoescape based on my clinically relevant preliminary data, using BCMA CART cell as a model. The central hypothesis is cancer-associated fibroblast (CAFs) induce CART dysfunction through complex mechanisms and that dual targeting of tumor cells and CAFs is safe and enhances the efficacy of CART cell therapy. To test this hypothesis, I have designed three specific aims: Aim #1) Determine the mechanisms of CAF-induced BCMA CART cell dysfunction in MM patients; Aim #2) Study the potential toxicity of dual targeting CART cells in syngeneic humanized MM-tumor microenvironment (TME) models; Aim #3) Utilize samples from patients who were treated with BCMA CART cell therapy to study the interactions between CAFs and CART cells. The rationale for this proposal is that in my established MM-TME model, CART cell trafficking to the tumor site is significantly inhibited. My preliminary data also showed that CAFs suppressed CART cell functions by secreting TGF-β and inhibitory cytokines as well as altering the PD-1/PD-L1 axis. Dual targeting tumor cells and CAFs significantly improved CART cell functions. This research will be significant because it will contribute depth (of understanding the CART cell resistance) and breadth (of novel potentially curative therapy) to the immunotherapeutic strategy against not just MM but also solid tumors. Ultimately, such discoveries have the potential to vertically advance the field of CART cell immunotherapy as well as other targeted immunotherapies. This project is innovative because it combines high throughput screening techniques to study the possible mechanisms of resistance after immunotherapy and, therefore, to generate novel treatments. The proposed research activities are crucial to the development of the applicant as an independently funded scientist with a focus on cellular immunotherapy. I will receive further training in molecular biology, translational medicine, and immunology from my mentors and training in cancer biology and bioinformatics from experienced collaborators at the Mayo Clinic. Therefore, at the conclusion of the training period, I will have acquired a unique set of intellectual and technical skills that will allow me to promote myself to become an independent translational researcher.

项目总结/文摘