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

• 批准号: 10634689
• 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
• 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/10634689
• 关键词: Antigen-Presenting Cells; 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; Cytoplasm; 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; Proliferating; Receptor Signaling; Recurrence; Relapse; Residual Neoplasm; 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; immune stimulatory agent; improved; in vivo; latent HIV reservoir; neoplastic cell; novel; novel strategies; prevent; receptor; resilience; response; scaffold

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.

艾滋病毒感染个体的免疫系统无法消除重生后潜在感染的细胞， 停止抗逆转录病毒疗法后，导致病毒血症复发，以防止功能治愈。这 需要艾滋病毒（PWH）的人终身艺术。需要采取新策略来动员免疫系统 为了防止在停止艾滋病毒后，艾滋病毒水库出现艾滋病毒。我们最近开发了Santacs， 不可用的免疫刺激生物制剂，由连接MHC分子和 病毒衍生的肽（C-PMHC），能够输送供应的抗原特异性TCR信号和配体 定义的共刺激信号。我们证明了带有CMV衍生肽和抗CD28的语法 SCFV或4-1BBL信号传导模块，刺激剧烈和选择性的离体和体内膨胀 PWH PBMC中的多功能CMV特异性CD8+ T细胞，在体内抗CMV活性表现出有效的效果。我们 最近还描述了CAR-T细胞的体外和体内抗HIV活性 分子Duocar结构可共表达两辆独立的汽车，每辆车都识别出不同的GP120表位。 HIV特异性的T细胞反应或CAR-T细胞处理无法提供对HIV感染的持续控制，因为 最终减少或丧失其功能性抗HIV活性，即使没有突变免疫 逃脱。相反，CMV特异性T细胞响应由效应器记忆CD8 T细胞组成，它们保持其 细胞因子释放，杀死和增殖的能力并实际上随着时间的推移而扩展，一种被称为的表型 记忆通胀。我们假设结合了语法的激活能力并显着扩展了CMV- 具有新型策略以重定向它们以消除HIV感染细胞的特定CD8 T细胞，将利用高度 功能和弹性CMV特异性CD8 T细胞反应可改善HIV感染的免疫控制。 我们建议结合义面有选择性激活并显着扩展CMV特异性CD8的能力 具有有效且持续的抗病毒活性的T细胞具有三个特定目的（SA），以重定向将其靶向HIV- 感染细胞。我们要么将扩展的CMV CD8 T细胞转换为HIV特异性的CAR T细胞（SA 1），要么 抗HIV T细胞（SA 2），或修改Santac结构以将CMV-C-PMHC，GP120界限和costumulation连接起来 配体，完全激活和直接CMV CD8 T细胞靶向HIV感染的细胞（SA 3），从而动员 控制HIV感染的体内免疫反应，消除了重新激活的潜在感染细胞，并提供 对PWH的艾滋病毒感染持续无艺术缓解。此外，我们还将利用交付的anttacs 定义的共刺激信号，以扩展我们有关不同共刺激信号能力的知识 生成最有效的CD8+ T细胞和CAR-T细胞，以消除重新激活的潜在感染T细胞。