Allogeneic cytotoxic gammadelta T cells for HIV cure immunotherapy

用于 HIV 治愈免疫治疗的同种异体细胞毒性 γδ T 细胞

• 批准号: 10256995
• 负责人: Natalia Soriano-Sarabia
• 金额: $ 23.44万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256995
• 关键词: Address; Adoptive Cell Transfers; Agonist; Allogenic; Anatomy; Antibodies; Autologous; Autologous Transplantation; B-Lymphocytes; BLR1 gene; Biological Assay; CD28 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Transplantation; Cells; Clinic; Clinical; Development; Effector Cell; Environment; FCGR3B gene; Face; Foundations; Frequencies; Future; Generations; Growth Factor; HIV; HIV Infections; Homologous Transplantation; Immune; Immune response; Immunotherapy; In Vitro; Interferon Type II; Interleukin-12; Interleukin-15; Interleukin-18; Interleukin-2; Interleukins; Investigation; Malignant - descriptor; Malignant Neoplasms; Mediating; Memory; Modeling; Natural Killer Cells; Notch Signaling Pathway; Oncology; Outcome; Pathway interactions; Phenotype; Population; Production; Property; Protocols documentation; Recovery; Reporting; Rest; Role; Shock; Surface; System; T cell response; T-Lymphocyte; Translating; Up-Regulation; Viral; Viral reservoir; adaptive immune response; base; chemokine receptor; clinical application; cytokine; cytotoxic; cytotoxic CD8 T cells; cytotoxicity; effector T cell; exhaustion; experimental study; functional plasticity; high reward; high risk; latent HIV reservoir; leukemia; mevalonate; migration; pamidronate; peripheral blood; receptor; γδ T cells

Allogeneic cytotoxic γδ T cells for HIV cure immunotherapy PROJECT SUMMARY HIV Cure strategies based on the “shock and kill” approach require the use of compounds to reactivate HIV from latency and potent immune responses to eliminate HIV-infected cells. Efforts have mostly focused on enhancing HIV-specific CD8 T cell responses but have faced a number of limitations including viral escape, immune exhaustion and inaccessibility to the B cell follicle. γδ T cells, specially the most abundant peripheral blood population, Vδ2 cells, constitute an attractive alternative cytotoxic cell population with unique properties largely exploited in adoptive cell therapies for different malignancies that we have started to explore for HIV cure purposes. In our previous studies, we showed that autologous Vδ2 γδ T cells from people living with HIV (PLWH) ART- suppressed are particularly effective inhibiting HIV replication and the first evidence that expanded Vδ2 cells target and eliminate HIV-infected resting CD4 T (rCD4) T cells after latency reversal. These studies constitute the basis for further investigation towards translating this alternative approach into the clinic. Vδ2 cells recognize intermediates of the mevalonate pathway in an MHC-unrestricted fashion. They respond to a given challenge by both up and/or downregulating specific receptors depending on the infectious/malignant environment displaying a unique functional plasticity that enables them i) to exert direct cytotoxicity and ii) to initiate and boost adaptive immune responses. Vδ2 cell phenotype can be shaped by ex vivo manipulating the mevalonate pathway using Aminobisphosphonates (nBPs) and IL-2 or IL-15 leading to Vδ2 cell activation and expansion. Similarly, to NK cells, combination of IL-2 and IL-15 with other cytokines and factors may favor the development of an effector memory phenotype with enhanced cytolytic activity against HIV-infected cells. Additionally, the lack of MHC restriction would allow for an allogeneic adoptive γδ T cell immunotherapy, that would be required for HIV cure since Vδ2 cells are targets of HIV infection. Allogeneic adoptive cell transfer has been explored in the cancer field and merits further investigation for HIV cure. Exploiting these unique features would allow the generation of a cytotoxic effector population with phenotypic and functional properties suited for targeting reactivated HIV- infected cells. Given Vδ2 cell functional plasticity, we hypothesize that manipulation of the mevalonate pathway and proper cytokine combinations will allow generation of a universal cytotoxic effector cell product of ex vivo expanded allogeneic Vδ2 cells that will recognize and kill HIV-infected cells upon latency reversal. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) to determine whether allogeneic expanded Vδ2 cells efficiently target and eliminate HIV-infected cells upon latency reversal and (2) to explore conditions to develop a universal immunotherapy Vδ2 effector cell product for HIV cure, and mechanisms of HIV-infected cell recognition.

用于 HIV 治愈免疫治疗的同种异体细胞毒性 γδ T 细胞 项目概要 基于“休克和杀灭”方法的艾滋病毒治疗策略需要使用化合物来重新激活艾滋病毒 潜伏期和有效的免疫反应可以消除感染艾滋病毒的细胞。努力主要集中在增强 HIV特异性CD8 T细胞反应但面临许多限制，包括病毒逃逸、免疫 B 细胞滤泡耗尽且无法进入。 γδ T 细胞，特别是最丰富的外周血 Vδ2 细胞群体构成了一种有吸引力的替代细胞毒性细胞群体，在很大程度上具有独特的特性 用于治疗不同恶性肿瘤的过继细胞疗法，我们已开始探索艾滋病毒治愈方法 目的。 在我们之前的研究中，我们发现来自 HIV 感染者 (PLWH) ART 的自体 Vδ2 γδ T 细胞 抑制特别有效地抑制 HIV 复制，并且是扩增 Vδ2 细胞的第一个证据 潜伏期逆转后，靶向并消除 HIV 感染的静息 CD4 T (rCD4) T 细胞。这些研究构成 进一步研究将这种替代方法转化为临床的基础。 Vδ2 细胞识别 以 MHC 不受限制的方式甲羟戊酸途径的中间体。他们通过以下方式应对给定的挑战 根据显示的感染性/恶性环境，上调和/或下调特定受体 独特的功能可塑性使它们能够 i) 发挥直接细胞毒性，ii) 启动和增强适应性 免疫反应。 Vδ2 细胞表型可以通过离体操纵甲羟戊酸途径来形成 氨基二磷酸盐 (nBP) 和 IL-2 或 IL-15 导致 Vδ2 细胞激活和扩增。同样，对于NK 细胞中，IL-2 和 IL-15 与其他细胞因子和因子的组合可能有利于效应子的发展 记忆表型，对 HIV 感染细胞具有增强的细胞溶解活性。此外，MHC 缺乏 限制将允许同种异体过继性 γδ T 细胞免疫疗法，这是治愈 HIV 所必需的 因为Vδ2细胞是HIV感染的目标。同种异体过继细胞移植已在癌症中得到探索 领域并值得进一步研究艾滋病毒治疗。利用这些独特的功能将允许生成 具有表型和功能特性的细胞毒性效应器群体，适合针对重新激活的 HIV- 被感染的细胞。 鉴于 Vδ2 细胞功能可塑性，我们假设甲羟戊酸途径的操纵和适当的 细胞因子组合将允许产生离体扩增的通用细胞毒性效应细胞产物 同种异体 Vδ2 细胞将在潜伏期逆转后识别并杀死 HIV 感染细胞。这些假设将 实验中要解决以下具体目的： (1) 判断是否同种异体扩增 Vδ2 细胞在潜伏期逆转后有效地靶向并消除 HIV 感染细胞，并且 (2) 探索条件 开发通用免疫治疗Vδ2效应细胞产品用于HIV治愈，以及HIV感染细胞的机制 认出。