Development of a treatment for the durable remission of HIV using autologous human CAR T cells that target B cell follicles

摘要 MarPam Pharma正在开发一种一次性治疗方法，用于持久缓解人类免疫缺陷病毒 (艾滋病毒)用于接受抗逆转录病毒治疗(ART)的患者。这种疗法是一种自体HIV特异性嵌合体。 使用CXCR5趋化因子受体的抗原受体(CAR；具体地说，CD4-MBL-CAR)T细胞治疗 作为一种归巢装置，将抗HIV杀手T细胞引导到位于淋巴滤泡1、2、2的“隐藏的”病毒库中 细胞滤泡是一种免疫保护部位，在这里大多数病毒复制可以相对有增无减地发生 CD4+T细胞3-7，可能是因为里面的病毒特异性CD8 T细胞比外面的明显少 淋巴组织中B细胞滤泡的数量8-11。事实上，很少有病毒特异性CD8 T细胞表达卵泡归巢 分子CXCR510，可能解释了体内靶向vRNA+细胞水平的效应器CTL降低40倍的原因 与B细胞滤泡外10相比。这些发现表明，HIV特异性CD8 T细胞无法 完全抑制病毒复制可能是由于B细胞滤泡缺乏病毒特异性CD8T细胞所致。 重要的是，这种CAR-T细胞治疗的初步研究表明，在动物身上是安全的，也成功地归巢了 CAR-T细胞到B细胞滤泡，CAR-T细胞与病毒RNA+感染细胞直接接触的证据，以及 感染猴免疫缺陷病毒(SIV)的ART抑制猕猴的病毒载量降低， 一种艾滋病毒的模型。在这里，我们建议进行一项启用IND的临床前研究，以评估其安全性和有效性 在一项统计上支持的研究中，将自体CAR-T细胞与人类CAR构造进行转导 在恒河猴-人类免疫缺陷病毒(SHIV)艾滋病毒模型中展示有效性。在我们的 最近的STTR1期研究，我们利用一项小规模的研究成功地制造了人类CAR-T细胞 方法。在这里，我们建议开发一种可扩展的方法来生产GMP，以生产伽马逆转录病毒和 CAR/CXR5-T细胞。这些拟议的研究将使我们的产品从目前的临床前阶段 发展为临床开发。

ABSTRACT MarPam Pharma is developing a one-time treatment for durable remission of human immunodeficiency virus (HIV) for patients treated with antiretroviral therapy (ART). This treatment is an autologous HIV-specific chimeric antigen receptor (CAR; specifically, CD4-MBL-CAR) T cell therapy that employs the CXCR5 chemokine receptor as a homing device to direct anti-HIV killer T cells into “hidden” viral reservoirs located in lymphoid follicles1,2. B cell follicles are an immune protected site where the majority of viral replication can occur relatively unabated in CD4+ T cells3-7, likely due to a markedly lower presence of virus-specific CD8 T cells inside compared to outside of B cell follicles in lymphoid tissue8-11. In fact, few virus-specific CD8 T cells express the follicular homing molecule CXCR510, possibly explaining the 40-fold lower in vivo effector CTL to target vRNA+ cell levels inside compared to outside of B cell follicles10. These findings suggest that the inability of HIV-specific CD8 T cells to fully suppress virus replication may be due to a deficiency of virus-specific CD8 T cells in B cell follicles. Importantly, pilot studies of this CAR-T cell treatment showed safety in animals and also successful homing of CAR-T cells to B cell follicles, evidence of direct contact of the CAR-T cells with viral RNA+ infected cells, and decreased viral loads in ART-suppressed rhesus macaques infected with simian immunodeficiency virus (SIV), a model of HIV. Here, we propose to conduct an IND-enabling preclinical study to assess the safety and efficacy of autologous CAR-T cells transduced with the human CAR construct in a study statistically powered to demonstrate efficacy in a rhesus macaque simian-human immunodeficiency virus (SHIV) model of HIV. In our recent STTR Phase 1 studies, we successfully produced human CAR-T cells using a small-scale research method. Here, we propose to develop a scalable method for GMP production of gammaretrovirus and CAR/CXR5-T cells. These proposed studies will move our product from the current preclinical stage of development into clinical development.