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正在开发一种持久缓解人类免疫缺陷病毒的一次性治疗方法 (HIV)接受抗逆转录病毒治疗（ART）的患者。这种治疗是一种自体HIV特异性嵌合 抗原受体（CAR;特别是CD4-MBL-CAR）采用CXCR5趋化因子受体的T细胞疗法 作为引导抗HIV杀伤T细胞进入位于淋巴滤泡中的"隐藏"病毒库的归巢装置1，2。B 细胞滤泡是一个免疫保护部位，在那里大多数病毒复制可以相对不减弱地发生， CD4 + T细胞3 - 7，可能是由于与外部相比，内部病毒特异性CD8 T细胞的存在显著降低 淋巴组织中的B细胞滤泡8 - 11。事实上，很少有病毒特异性CD8 T细胞表达滤泡归巢， 分子CXCR510，可能解释了体内效应CTL对靶向vRNA+细胞水平的40倍低， 与B细胞滤泡外相比10.这些发现表明，HIV特异性CD8 T细胞不能 完全抑制病毒复制可能是由于B细胞滤泡中缺乏病毒特异性CD8 T细胞。 重要的是，这种CAR-T细胞治疗的初步研究显示了在动物中的安全性，并且还成功地将CAR-T细胞归巢。 CAR-T细胞至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 在感染猴免疫缺陷病毒（SIV）的ART抑制恒河猴中降低病毒载量， 艾滋病病毒的模型。在这里，我们建议进行一项IND使能临床前研究，以评估安全性和有效性 在一项统计学上有把握的研究中， 在HIV的恒河猴猴-人免疫缺陷病毒（SHIV）模型中显示出有效性。在我们 在最近的STTR第1阶段研究中，我们使用小规模研究成功地生产了人类CAR-T细胞。 法在这里，我们提出开发一种用于GMP生产γ逆转录病毒的可扩展方法， 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， 发展到临床开发。

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.