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

基本信息

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
项目类别：
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

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

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项目摘要

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.

同种异体细胞毒性γδT细胞用于HIV治疗免疫疗法项目摘要艾滋病毒基于“震惊与杀戮”方法的治疗策略需要使用化合物重新激活艾滋病毒潜伏期和潜在免疫复杂，以消除感染HIV的细胞。努力主要集中于增强 HIV特异性的CD8 T细胞反应，但面临许多局限性，包括病毒逃生，免疫 B细胞植物的精疲力尽和无法获得。 γδT细胞，特别是最丰富的外周血种群Vδ2细胞构成具有独特特性的吸引人的替代细胞毒性细胞种群在自适应细胞疗法中利用我们已经开始探索艾滋病毒治疗的不同malignancys 目的。在我们先前的研究中，我们表明来自HIV（PLWH）ART-患者的自体Vδ2γδT细胞被抑制是特别有效抑制HIV的复制，也是第一个扩展Vδ2细胞的证据靶标并消除潜伏期反转后的HIV感染的静息CD4 T（RCD4）T细胞。这些研究构成将这种替代方法转化为诊所的进一步研究的基础。 Vδ2细胞识别 MHC无限制的时尚中间人的中间体。他们应对给定的挑战取决于传染性/恶性环境，向上和/或下调特定的接收器使它们能够执行直接细胞毒性的独特功能可塑性，ii）启动和增强自适应免疫反应。 VΔ2细胞表型可以通过使用实体操纵甲谷酸盐途径来塑造氨基偶氮磷酸盐（NBPS）和IL-2或IL-15导致Vδ2细胞激活和膨胀。同样，到NK 细胞，IL-2和IL-15与其他细胞因子的组合以及因子可能有利于效应子的发展对艾滋病毒感染细胞的细胞溶解活性增强的记忆表型。此外，缺乏MHC 限制将允许同种异体适应性γδT细胞免疫疗法，这是HIV治疗所必需的由于Vδ2细胞是HIV感染的靶标。在癌症中探索了同种异体自适应细胞转移现场并值得进一步研究HIV治疗。利用这些独特的功能将允许产生具有表型和功能特性的细胞毒性效应人群，适用于靶向重新激活的HIV- 感染细胞。给定Vδ2细胞功能可塑性，我们假设对甲谷酸盐途径的操纵和正确细胞因子组合将允许生成Ex Vivo的通用细胞毒性效应细胞产物扩展同种异体Vδ2细胞将在潜伏期逆转后识别并杀死感染HIV感染的细胞。这些假设会在以下特定目的的实验中解决：（1）确定同种异体是否扩展 Vδ2细胞有效地靶向并消除潜伏期后的HIV感染细胞，（2）探索条件开发用于HIV治疗的通用免疫疗法Vδ2效应细胞产物和HIV感染细胞的机制认出。