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Democratizing CAR T cell therapy by in situ programming of virus-specific T cells

通过病毒特异性 T 细胞的原位编程使 CAR T 细胞疗法大众化

基本信息

批准号：
10739646
负责人：
Fang-Yi Su
金额：
$ 11.09万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-08 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739646
关键词：
Adoptive Transfer Advisory Committees Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Autoimmune B-Lymphocytes Benchmarking Biodistribution Biological Assay Biotinylation Blood Bypass CAR T cell therapy CD19 gene CRISPR therapeutics CRISPR/Cas technology Cancer Model Cancer Patient Cell Line Cell Maturation Cells Cellular biology Clinical Coculture Techniques DNA Democracy Development Disease Progression Doctor of Medicine Doctor of Philosophy Dose Effectiveness Encapsulated Environment Epitopes Face Flow Cytometry Frequencies Future Genes Genome Genome engineering Goals HLA-A gene HLA-A2.1 Hematologic Neoplasms Hematology Histocompatibility Antigens Class I Human Immunity Immunotherapy In Situ Influenza Influenza A virus Influenza vaccination Kinetics Knowledge Lead Lentivirus Liver Major Histocompatibility Complex Malignant Neoplasms Memory Mentors Mentorship Messenger RNA Multiple Myeloma Mus Oncology Patients Peptides Peripheral Blood Mononuclear Cell Phase Phenotype Polymers Population Production Recombinants Regulatory T-Lymphocyte Research Resources Safety Self Tolerance Specificity Spleen Stains System T cell differentiation T cell therapy T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Studies Time Toxic effect Transfection Transgenes Translations Treatment Efficacy Treatment outcome Universities Vaccinated Vaccination Viral Virion Virus Virus Diseases Work anti-cancer anticancer activity antigen-specific T cells antiviral immunity bioluminescence imaging cancer cell cancer therapy career cell killing cell type chimeric antigen receptor chimeric antigen receptor T cells cohort cost cost efficient cytokine cytotoxicity engineered T cells exhaustion experimental study improved in vivo influenza infection influenzavirus lipid nanoparticle manufacture manufacturing process mouse model nanoparticle new technology novel strategies peptide I programs proliferation potential receptor receptor expression recombinant virus seasonal influenza success unvaccinated vaccination strategy

项目摘要

Engineered T cells that express chimeric antigen receptors (CARs) have shown remarkable efficacy against hematological malignancies. However, broad implementation of CAR T cell therapies is limited by the lengthy (3–5 weeks) and costly ($350K–450K per treatment) ex vivo manufacturing pipeline. This proposal seeks to develop antigen-presenting nanoparticles (APNs) for in situ programming of virus-specific T cells for rapid and cost-efficient CAR T cell manufacturing. Virus-specific T cells present a promising opportunity to enhance CAR T cell therapy, as they have improved persistence and proliferation potential, and allow for viral vaccination to augment CAR therapy through their endogenous receptors. This proposal will focus on influenza A virus (IAV)- specific T cells to exploit the existing seasonal influenza vaccination to boost CAR activities. To deliver CAR to IAV-specific T cells, APNs will comprise lipid nanoparticles (LNPs) that encapsulate CAR-encoded mRNA and are decorated with HLA-A peptide-major histocompatibility complex (pMHC) displaying influenza peptide epitopes. This proposal will use APNs to deliver human B-cell maturation antigen (BCMA) CAR in the context of multiple myeloma with future goals to expand to other CAR specificities and indications, including CD19 positive cancers. The goal in Aim 1 is to develop APNs for transfection of human influenza-specific T cells with αBCMA CAR in vivo, and characterize the CAR transfection specificity in the target IAV-specific T cells versus other major cell populations. Aim 2 will be focused on validating the anti-cancer efficacy of αBCMA CAR T cells after in situ transfection using a mouse model recapitulating human multiple myeloma. The vaccination strategy to expand IAV-specific T cells and to boost their effector functions will be tested using inactivated influenza virions to vaccinate the CAR-expressing, IAV-specific T cells and compare the resulting anti-cancer potency with the unvaccinated cohort. In Aim 3, CRISPR/Cas9 will be implemented with APNs for in vivo gene editing of T cells with CAR for durable CAR expression and enhanced anti-cancer potency by delaying T-cell differentiation and exhaustion. The success of this proposal will challenge existing paradigms of T cell engineering, reduce the cost of CAR T cell therapy, and enhance anti-cancer activity through influenza vaccination to ultimately democratize CAR T cells for cancer therapy. Through this work, the candidate will close the knowledge gaps by the mentorship of an exceptional advisory committee: (1) Gabe Kwong, Ph.D. (CAR T cell engineering), (2) Phil Santangelo, Ph.D. (mRNA therapeutics and CRISPR/Cas), (3) Rafi Ahmed, Ph.D. (anti-viral T cell immunity and memory/exhaustion T cell biology), and (4) Madhav Dhodapkar, M.D. (hematology/oncology and myeloma cancer models). This strong mentoring team and the abundant resources provided by Georgia Tech and Emory University constitute a fertile mentoring environment for attaining the candidate's career goal of leading an independent research program focused on developing new technologies to improve patient access and treatment outcome of T-cell immunotherapy against cancer.

表达嵌合抗原受体（CARs）的工程化T细胞已显示出显著的抗