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Amplifying and Redirecting CMV-specific CD8 T cells to provide sustained control of HIV infection

扩增和重定向 CMV 特异性 CD8 T 细胞以持续控制 HIV 感染

基本信息

批准号：
10548600
负责人：
STEVEN C. ALMO
金额：
$ 84万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2022-06-03 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548600
关键词：
Antigens Architecture Biological Biological Products Bispecific Antibodies CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Chronic Clinical Coupled Cytokine Signaling Cytomegalovirus Cytomegalovirus Infections Development Disease remission Epitopes Exhibits Fc domain HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Immune Immune checkpoint inhibitor Immune response Immune system Immunity Immunotherapeutic agent In Vitro Individual Infusion procedures Knowledge Lentivirus Vector Ligands Link Malignant Neoplasms Memory Mutation Patients Peptide/MHC Complex Peptides Peripheral Blood Mononuclear Cell Persons Phenotype Production Receptor Signaling Recurrence Relapse Residual Tumors Resistance Signal Transduction Structure T cell response T memory cell T-Cell Receptor T-Lymphocyte Time Viral Viral Physiology Viremia Virus antigen-specific T cells antiretroviral therapy chimeric antigen receptor T cells chronic infection cytokine cytotoxic CD8 T cells design dimer engineered T cells exhaustion improved in vivo latent HIV reservoir neoplastic cell novel novel strategies prevent receptor response scaffold

项目摘要

The immune system of HIV-infected individuals is unable to eliminate latently infected cells following reactivation, resulting in the recurrence of viremia after stopping antiretroviral therapy, preventing functional cure. This necessitates lifelong ART for people with HIV (PWH). New strategies are needed to mobilize the immune system to prevent the emergence of HIV from the HIV reservoir after ART cessation. We recently developed synTacs, infusible immunostimulatory biologics consisting of dimeric Fc-domain scaffolds linking MHC molecules and virus-derived peptides (c-pMHC) capable of delivering antigen-specific TCR-signals and ligands that supply defined costimulatory signals. We demonstrated that synTacs bearing CMV-derived peptides, and anti-CD28 scFv or 4-1BBL signaling modules, stimulated vigorous and selective ex vivo and in vivo expansion of highly polyfunctional CMV-specific CD8+ T cells in PWH PBMC, which displayed potent in vivo anti-CMV activities. We also recently described the potent in vitro and in vivo anti-HIV activity of CAR-T cells that use a novel two- molecule duoCAR architecture to co-express two independent CARs, each recognizing a distinct gp120 epitope. HIV-specific T cell responses or CAR-T cell treatments fail to provide sustained control of HIV infection because of the eventual reduction or loss of their functional anti-HIV activity, even in the absence of mutational immune escape. In contrast, CMV-specific T cell responses consist of effector memory CD8 T cells that maintain their capacity for cytokine release, killing and proliferation and actually expand over time, a phenotype described as memory inflation. We hypothesize that combining the capacity of synTacs to activate and markedly expand CMV- specific CD8 T cells with novel strategies to redirect them to eliminate HIV-infected cells, would exploit the highly functional and resilient CMV-specific CD8 T cell responses to provide improved immune control of HIV infection. We propose to combine the capacity of synTacs to selectively activate and markedly expand CMV-specific CD8 T cells with potent and sustained anti-viral activity with three Specific Aims (SA) to redirect them to target HIV- infected cells. We will either convert the expanded CMV CD8 T cells into HIV-specific CAR T cells (SA 1), or anti-HIV T cells (SA 2), or modify the synTac structure to link CMV-c-pMHC, gp120-binders and costimulatory ligands, to both fully activate and direct CMV CD8 T cells to target HIV-infected cells (SA 3), thereby mobilizing an in vivo immune response that controls HIV infection, eliminates reactivated latently infected cells and provides sustained ART-free remission of HIV infection to PWH. Furthermore, we will also utilize synTacs delivering defined costimulatory signals, to extend our knowledge regarding the capacity of different costimulatory signals to generate the most potent CD8+ T cells and CAR-T cells for eliminating reactivated latently infected T cells.

hiv感染者的免疫系统在重新激活后无法消除潜伏感染的细胞，