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Modeling HIV CAR-T cell trafficking and persistence in Non-Human Primates

模拟 HIV CAR-T 细胞在非人类灵长类动物中的运输和持久性

基本信息

批准号：
10450650
负责人：
HANS-PETER KIEM
金额：
$ 74.06万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450650
关键词：
Address Animals Antigens Autologous Autopsy B-Cell Leukemia B-Lymphocytes Benchmarking Biological Assay Brain CCR5 gene CD19 gene CXCR4 gene Cell Line Cell Therapy Cell surface Cells Chimeric Proteins Chromosome Mapping Cryopreservation Data Engraftment Environment Flow Cytometry Gene Expression Profiling Gene-Modified Genes Goals Gold Gut associated lymphoid tissue HIV HIV Infections Hematologic Neoplasms Hematopoietic stem cells Immune Immunohistochemistry Individual Infection Injections Lead MS4A1 gene Macaca Measurement Measures Mediating Modeling Modification Neuraxis Nucleic Acids Paraffin Embedding Patients Pattern Phenotype Play Property Research Resistance to infection Sampling Secondary to Signal Transduction Site Solid Neoplasm Surface Surface Antigens T memory cell T-Lymphocyte Tissues Tumor Antigens Viral reservoir Virus Virus Diseases Virus Latency Virus Replication Withdrawal Work antiretroviral therapy base chimeric antigen receptor chimeric antigen receptor T cells density design engineered T cells experimental study gene therapy human disease in vivo in vivo Model insight interest leukemia lymph nodes migration nonhuman primate paraform prevent simian human immunodeficiency virus success trafficking tumor microenvironment zinc finger nuclease

项目摘要

Project 2 - Abstract Modification of autologous T-cells with chimeric antigen receptor (CAR) molecules has revolutionized the treatment of many leukemias, and is designed to enable “plug and play” targeting of any surface-expressed marker of human disease. We are interested in optimizing CAR-T therapies for persistent HIV-1 infection. Importantly, although the list of hematological malignancies to which CAR-T can be applied is rapidly expanding, several barriers have prevented application to HIV+ individuals. First and foremost, CAR-T function is frequently downregulated or lost upon migration to tissues, for example limiting targeting of solid tumors. This also represents a key limitation for targeting of latently HIV-1 infected cells that reside at sites including lymph nodes, gut, and the brain. Furthermore, increasing evidence suggests that in order for CAR-T to recognize their cognate targets, a threshold level of antigen expression may be required at the target cell surface. The central goal of our U19 consortium is to understand the fate of a CAR T-cell in vivo. In our project, we will compare virus-specific CARs to CARs directed against CD20+ leukemias, mechanisms of action in antigen-rich vs. antigen-sparse environments, and the ability of CAR-T to maintain potent, target-specific function after migrating to secondary tissue sites known to harbor latent virus. We will address these questions in our well-established nonhuman primate (NHP) model of suppressed HIV-1 infection, focusing on the optimized CD4CAR molecule developed by Dr. Riley in Project 3. We will first compare CD4CAR-T to a previously-characterized NHP version of the successful, leukemia-targeting CD20 CAR molecule (“NHP CD20 CAR-T”), in 6 uninfected animals. Next, we will focus on CD4CAR-T in 12 animals that have been previously infected with simian/human immunodeficiency virus (SHIV) and suppressed by antiretroviral therapy (ART). Our studies in a total of 18 uninfected or infected, suppressed animals will provide unprecedented insights into the mechanisms that promote engraftment, persistence, and function in vivo, and/or lead to silencing or inhibition of antigen-dependent expansion. We have chosen the NHP model for our studies, as a key aspect of our approach is to better understand CAR-T trafficking and function in tissues. Using well-established assays to measure tissue resident memory T-cells (TRM), along with immunohistochemistry and transcriptional profiling approaches, we will characterize CD4CAR-T function in low and high antigen environments (i.e. before and after release of ART), and ii) benchmark these activities against our positive control, NHP CD20 CAR-T. Our NHP research aims will apply the gold standard for in vivo modeling of suppressed HIV infection, and are highly complementary to experiments proposed in Project 1/Wherry, Project 3/Riley, and Project 4/Coughlin and Tebas.

项目2 -摘要