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: 10383737
• 负责人: Natalia Soriano-Sarabia
• 金额: $ 20.19万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383737
• 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; Donor person; 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; Persons; 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.

同种异体细胞毒γδT细胞用于治疗艾滋病的免疫治疗 项目总结 基于“休克和杀死”方法的艾滋病毒治疗策略要求使用化合物从 潜伏期和强大的免疫反应，以消除艾滋病毒感染细胞。这些努力主要集中在加强 HIV特异的CD8 T细胞反应，但面临着一些限制，包括病毒逃逸、免疫 精疲力竭和无法接触到B细胞滤泡。γδT细胞，特别是最丰富的外周血液 群体，Vδ2细胞，构成了一个有吸引力的替代细胞毒性细胞群体，主要具有独特的性质 我们已经开始探索针对不同恶性肿瘤的过继细胞疗法来治愈艾滋病毒 目的。 在我们之前的研究中，我们表明来自艾滋病毒携带者(PLWH)的自体Vδ2γδT细胞-ART- 被抑制的是特别有效地抑制艾滋病毒复制和第一个证据表明扩增的Vδ2细胞 潜伏期逆转后，靶向并消除HIV感染的静息CD4T(RCD4)T细胞。这些研究构成了 为进一步研究将这一替代方法应用于临床奠定了基础。V-δ-2细胞识别 甲氧丙戊酸途径的中间体，不受MHC限制。他们通过以下方式回应给定的挑战 根据感染/恶性环境的表现，上调和/或下调特定受体 一种独特的功能可塑性，使它们能够：1)发挥直接的细胞毒性；2)启动和增强适应性 免疫反应。V-δ-2细胞表型可以通过体外操纵甲羟戊酸途径来形成。 氨基双膦酸盐(NBPS)和IL-2或IL-15可激活和扩增V-δ-2细胞。同样，对于NK来说 细胞、IL-2和IL-15与其他细胞因子和因子的结合可能有利于效应器的发展 对HIV感染细胞具有增强的细胞溶解活性的记忆表型。此外，缺乏MHC 限制将允许同种异体过继γδT细胞免疫疗法，这是治愈艾滋病毒所必需的 因为Vδ2细胞是艾滋病毒感染的目标。同种异体过继细胞移植在癌症中已被探索 在艾滋病的治疗领域值得进一步研究。利用这些独特的功能将允许生成 一种具有表型和功能特性的细胞毒效应群，适合靶向重新激活的HIV- 被感染的细胞。 鉴于Vδ2细胞的功能可塑性，我们假设甲氧戊酸途径的操纵和适当的 细胞因子组合将允许产生体外扩增的通用细胞毒效应细胞产品 潜伏期逆转后识别并杀死感染艾滋病毒的细胞的同种异体Vδ2细胞。这些假设将 在下列特定目的的实验中被解决：(1)确定同种异体是否扩大 Vδ2细胞在潜伏期逆转后有效靶向并清除感染艾滋病毒的细胞和(2) 探索条件，以 开发一种通用免疫疗法V-δ-2效应细胞产品，用于治疗艾滋病病毒，并探讨其感染细胞的机制 承认。