HIV-specific ex-vivo expanded T cell therapy (HXTC) to Deplete the Latent Reservoir of Persistent HIV Infection

HIV 特异性体外扩增 T 细胞疗法 (HXTC) 可消除持续性 HIV 感染的潜在储库

• 批准号: 9889986
• 负责人: Catherine M. Bollard
• 金额: $ 73.53万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889986
• 关键词: Address; Adenoviruses; Allogenic; Antigens; Antiviral Agents; Archives; Autologous; Bypass; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Therapy; Cells; Combined Modality Therapy; Cytomegalovirus; Cytotoxic T-Lymphocytes; Data; Dose; Epitopes; Frequencies; Future; Goals; HIV; HIV Antigens; HIV Infections; HIV-1; Half-Life; Histone Deacetylase; Histone Deacetylase Inhibitor; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunologics; Immunotherapy; In Vitro; Individual; Infection; Infusion procedures; Innovative Therapy; Interphase Cell; Interruption; Malignant Neoplasms; Mutation; Participant; Patients; Pharmaceutical Preparations; Population; Residual state; Rest; Risk; Safety; T cell response; T cell therapy; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Transplantation; Vaccines; Variant; Viral; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Latency; Vorinostat; Work; antigen-specific T cells; antiretroviral therapy; appropriate dose; chronic infection; clinically relevant; cytotoxic; experience; immune function; in vivo; latent infection; novel; post-transplant; public health relevance; response; therapeutic vaccine; tool; virology

 DESCRIPTION (provided by applicant): The inability to eliminate HIV-1 from latently infected reservoirs remains the critical limitation to HIV eradication. One approach to eradicate HIV infection is to 1) expose latent, persistent HIV by interfering with mechanisms that maintain latency, and 2) eliminate exposed latently infected cells by enhanced T- cell immune response without interrupting ART. Studies have demonstrated that Histone Deacetylase (HDAC) is a critical regulator of HIV latency, and our own work has shown that the HDAC inhibitor, vorinostat (VOR), can induce the expression of latent HIV-1. As promising work on delineating effective dosing strategies for latency reversal in vivo using agents such as VOR is advancing, it is increasingly important to address how to effectively harness the immune response against latent HIV infection. One strategy to enhance the existing HIV immune response is adoptive T cell therapy using autologous, ex vivo expanded cytotoxic T lymphocytes (CTLs). This approach successfully treats virus-associated cancers and viral reactivation after transplant. While T cell therapy has proven to be safe in HIV patients, efficacy has been limited in the past. Here, we propose that an HIV-specific T cell product with broader recognition, unrestricted by HLA type, would increase the ability of the T-cells to target latently infected cells. We have developed a novel GMP compliant strategy to expand functional, broadly-specific T-cells (HXTCs) from patients on ART and hypothesize that in vivo administration of autologous ex vivo expanded HXTCs that recognize multiple HIV-1 antigens in HIV-infected participants on suppressive ART will a) be safe, b) increase in vivo, HIV-1 antigen specific T-cell immune responses and c) decrease resting cell infection when combined with the latency reversing agent, VOR. We will investigate whether CD8 T cell epitope targeting, immunodominance hierarchies, and viral escape mutations alter in vitro virus inhibition and in vivo levels of resting CD4 cell infection before and after HXTC infusion. This proposal builds upon the data generated by U01 AI095052, which has explored the anti-latency activity of VOR and defined optimal dosing strategies, with an ultimate goal to combine VOR with adoptive T cell therapy to induce a significant decrease in the frequency of persistent infection of resting CD4+ T cells.

 描述（由申请人提供）：无法从潜伏感染的病毒库中消除 HIV-1 仍然是根除 HIV 的关键限制。消除 HIV 感染的一种方法是 1）通过干扰维持潜伏的机制来暴露潜伏、持续的 HIV。 2) 在不中断 ART 的情况下，通过增强 T 细胞免疫反应消除暴露的潜伏感染细胞 研究表明，组蛋白脱乙酰酶 (HDAC) 是 HIV 潜伏期的关键调节因子，我们自己的工作也证实了这一点。研究表明，HDAC 抑制剂伏立诺他 (VOR) 可以诱导潜伏 HIV-1 的表达，随着利用 VOR 等药物在体内描绘有效剂量策略以逆转潜伏期的前景广阔，解决如何解决这一问题变得越来越重要。有效利用针对潜在 HIV 感染的免疫反应，增强现有 HIV 免疫反应的一种策略是使用自体、离体扩增的细胞毒性 T 淋巴细胞 (CTL) 进行过继性 T 细胞治疗，这种方法成功地治疗了病毒相关癌症。虽然 T 细胞疗法已被证明对 HIV 患者是安全的，但过去的疗效有限，我们建议，不受 HLA 类型限制的、具有更广泛识别性的 HIV 特异性 T 细胞产品将会增加。 T 细胞靶向潜伏感染细胞的能力 我们开发了一种符合 GMP 的新型策略，用于从接受 ART 的患者和指导员体内进行自体离体扩增的功能性、广泛特异性 T 细胞 (HXTC) 中扩增。 HXTC 在接受抑制性 ART 的 HIV 感染者中识别多种 HIV-1 抗原，将 a) 安全，b) 增加体内 HIV-1 抗原特异性 T 细胞免疫反应，c) 与潜伏期相结合，减少静息细胞感染我们将研究 CD8 T 细胞表位靶向、免疫显性层次和病毒逃逸突变是否会改变 HXTC 输注前后的体外病毒抑制和静息 CD4 细胞感染的体内水平。该提案以 U01 AI095052 生成的数据为基础，探索了 VOR 的抗潜伏活性并确定了最佳剂量策略，最终目标是将 VOR 与过继性 T 细胞疗法相结合，以显着降低持续感染的频率静息 CD4+ T 细胞。