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Overcoming the hurdles to successful CAR T cell therapy for a functional HIV cure

克服成功 CAR T 细胞疗法实现功能性 HIV 治愈的障碍

基本信息

批准号：
10477182
负责人：
Daniel Thomas Claiborne
金额：
$ 10.8万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477182
关键词：
Address Affect Animal Model Anti-Retroviral Agents Antigens Automobile Driving BLT mice Biological Models Blood Cells CAR T cell therapy CD4 Positive T Lymphocytes Career Mobility Cell Therapy Cell physiology Cells Cellular biology Chronic Clinic Clinical Trials Complex Cytotoxic T-Lymphocytes Data Development Development Plans Disease Engineering Functional disorder Funding Generations Genetic Engineering Goals Growth HIV HIV Infections HIV therapy Human Immune Immune System Diseases Immune response Immune system Immunity Immunology Individual Innate Immune System Intervention Knowledge Malignant Neoplasms Maps Methods Modality Modeling Morbidity - disease rate Natural Immunity Nature Pattern Pharmaceutical Preparations Phenotype Play Preventive vaccine Public Health Resistance Role Science Scientist Shock Source T cell response T memory cell T-Cell Activation T-Lymphocyte Testing Therapeutic Time Translating Variant Viral Viral Load result Viral reservoir Viremia Virus Virus Diseases Virus Replication adaptive immunity antigen-specific T cells antiretroviral therapy cancer cell career career development chimeric antigen receptor chimeric antigen receptor T cells cytotoxic exhaust exhaustion experimental study humanized mouse immune activation immune reconstitution immunopathology improved in vivo invention monocyte mortality mouse model novel pathogen programmed cell death protein 1 purge receptor skills success transcription factor transcriptome sequencing transcriptomics viral fitness virology

项目摘要

Project Summary/Abstract This proposal seeks the necessary funding to facilitate the career transition of Dr. Daniel Claiborne to an independent academic scientist. The original aims brought forth in this proposal build upon the basic HIV virology, immunology, and pathogen-host interaction expertise of the candidate and leverage these skills towards translational efforts in a small animal model aimed at achieving a functional HIV cure. Furthermore, the career development plan outlines a path towards acquiring valuable skills necessary for the execution of this proposal as well as the transition to independence. Finally, the data generated from the successful execution of these experiments will yield the preliminary data to apply for R01-level funding. The human immunodeficiency virus (HIV) promptly subverts the host cellular immune response through rapid viral escape and high antigen loads leading to chronic immune activation and T cell dysfunction. Combination antiretroviral therapy (ART) has drastically reduced the morbidity and mortality of HIV infection, but must be taken indefinitely as HIV persists in long-lived stable reservoirs and thus presents a significant public health burden. One approach to purging the viral reservoir, termed “shock and kill”, relies on latency reversing agents (LRAs) to reactivate latently infected cells such that they can be cleared by the immune system. However, clinical trials testing LRAs have achieved little success, perhaps due to the dysfunction of the natural cellular immune response. Genetic engineering modalities may offer an attractive alternative to intrinsic immunity. Chimeric antigen receptor (CAR) T cells re-engineered to target HIV using the CD4 ectodomain (CD4-CAR) represent an escape-resistant “kill” mechanism demonstrated to have enhanced cytotoxic function. Therefore, we hypothesized that CD4-CAR T cells would be a promising intervention capable of suppressing HIV replication and effectively targeting the viral reservoir. To rapidly test and optimize our approach, we made use of the BLT humanized mouse model of HIV infection. Our preliminary results demonstrate that CD4-CAR T cells respond robustly to antigen, expand up to 1000-fold in vivo, and significantly protect HIV-infected BLT mice from rapid CD4+ T cell loss. Furthermore, we improved the expansion potential and cytotoxic function of CD4-CAR T cells, and were able to protect CD4-CAR T cells from HIV infection. However, despite their ability to enhance viral suppression with ART, CAR T cell therapy alone was unable to durably suppress viremia in BLT mice. We propose to address this deficit in the following specific aims: 1) Determine the effect of viral replication capacity on CAR T cell efficacy, 2) map the ontogeny of exhausted CAR T cells in vivo, and 3) interrogate the role of the innate immune system in modulating CAR T cell function. Completion of these aims will enhance our understanding of the factors contributing to T cell dysfunction in chronic viral infections, with the hope of translating these findings towards a functional HIV cure.

项目总结/文摘