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.

同种异体细胞毒性γδ T细胞用于HIV治愈免疫疗法