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)：无法从潜伏感染的水库中消除艾滋病毒-1仍然是根除艾滋病毒的关键限制因素。根除HIV感染的一种方法是1)通过干扰维持潜伏期的机制来暴露潜伏的、持久的HIV，以及2)通过增强T细胞免疫反应在不中断ART的情况下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潜伏时间的关键调节因子，我们自己的工作表明HDAC抑制剂VOR(VOR)可以诱导潜伏的HIV-1的表达。随着使用VOR等药物描述体内潜伏期逆转的有效剂量策略的工作取得进展，如何有效地利用免疫反应对抗潜在的HIV感染变得越来越重要。增强现有HIV免疫应答的一种策略是使用自体、体外扩增的细胞毒性T淋巴细胞(CTL)进行过继T细胞治疗。这种方法成功地治疗了病毒相关性癌症和移植后的病毒重新激活。虽然T细胞疗法已被证明对艾滋病毒患者是安全的，但过去的疗效一直有限。在这里，我们建议，一种识别范围更广的HIV特异性T细胞产品，不受HLA型的限制，将增加T细胞靶向潜伏感染细胞的能力。我们开发了一种新的符合GMP的策略来扩增服用ART的患者的功能性、广谱特异性T细胞(HXTC)，并假设在抑制ART的HIV感染参与者体内给予识别多种HIV-1抗原的自体体外扩增的HXTC将a)是安全的，b)在体内增加HIV-1抗原特异的T细胞免疫反应，c)与潜伏期反转剂VOR联合使用时减少静息细胞感染。我们将研究在注射HXTC前后，CD8T细胞表位靶向、免疫优势等级和病毒逃逸突变是否会改变体外病毒抑制和体内静止CD4细胞感染水平。这项建议建立在U01 AI095052产生的数据基础上，该数据探索了VOR的抗潜伏期活性并定义了最佳剂量策略，最终目标是将VOR与过继T细胞治疗相结合，显著降低静息CD4+T细胞持续感染的频率。