A novel CAR-T cell therapy for the one-time treatment of chronic HIV infection in patients who are not ART suppressed

摘要 在我们成功的灵长类动物模型研究的基础上，我们的目标是开发一种一次性治疗持久缓解的方法 在没有抗逆转录病毒治疗(ART)的情况下，人类免疫缺陷病毒(HIV)的感染。这种靶向治疗 是一种自体HIV特异性嵌合抗原受体(CAR)-T细胞疗法，采用CXCR5“归巢” 设备“引导抗病毒杀手T细胞进入B细胞滤泡，在那里它们可以清除产生病毒的细胞。B细胞 由于低水平的病毒特异性CD8，毛囊是一种“隐藏的”免疫保护部位，允许病毒复制 T细胞。我们的临床前CAR/CXCR5-T细胞在猴免疫缺陷病毒(SIV)感染恒河猴中的初步研究 猕猴的HIV模型表明，这种免疫疗法在ART治疗的动物中是安全有效的。我们的 资助STTR快速通道赠款建议研究慢性感染的类似治疗方法 非艺术压抑的个体。在第一阶段研究中，我们将修改原始CAR/CXCR5 DNA结构以 使优化(OPT)CAR/CXCR5-T细胞具有更强的持久性、更高的抗病毒结合亲和力，以及 对SIV/HIV感染的抗药性。在第二阶段，我们将开发一种GMP可缩放的方法来生产人类 OptCAR/CXCR5-T细胞用于人类第一阶段临床试验，该方法将用于生产 猕猴optCAR/CXCR5-T细胞用于支持IND的临床前研究。支持IND的研究 将评估optCAR/CXCR5-T细胞在SIV慢性HIV感染模型中的安全性和有效性。这里, 我们建议参与I-Corp计划的团队包括：1)C级公司官员， 阿萨纳修博士；2)科学技术专家，森博士；和(3)行业专家，珍妮特·怀特。这支队伍将是 由MarPam联合创始人兼首席执行官、家长奖首席调查员玛丽亚·阿塔纳修博士领导。 阿塔纳修博士在药物开发方面有专业知识，曾领导一个团队开发了一种FDA批准的药物 在治疗抑郁症方面，管理着1亿美元的预算，并为市场研究做出了关键贡献 和营销活动。MarPam高级科学家Nandini Sen博士将作为技术专家参加。 在斯坦福大学担任高级科学家后加入MarPam，森博士为她带来了 在著名传染病安·阿文博士的实验室工作了十多年 斯坦福大学的专家。作为团队的补充，珍妮特·怀特是一位经验丰富的高管和行业专家 在国际生命科学公司工作了35年。除了她被证明的记录之外 在制定和实施增长战略和产品开发方面，她是 创业者和初创公司通过加速器和指导计划。所有团队成员都是 愿意在项目期间每周至少工作20个小时，并真诚地希望 调查围绕创新的商业景观。这支团队和公司将受益 来自i-Corps计划和MarPam C级公司官员承诺将 从这次市场研究中吸取教训，修改其商业化战略。

Abstract Building on our successful primate model studies, we aim to develop a one-time treatment for durable remission of human immunodeficiency virus (HIV) in the absence of antiretroviral therapy (ART). This targeted treatment is an autologous HIV-specific chimeric antigen receptor (CAR)-T cell therapy that employs a CXCR5 “homing device” to direct anti-viral killer T cells into B cell follicles where they can eliminate virus-producing cells. B cell follicles are a “hidden” immune protected site that permit viral replication due to low levels of virus-specific CD8 T cells. Our preclinical CAR/CXCR5-T cell pilot studies in a simian immunodeficiency virus (SIV)-infected rhesus macaque model of HIV indicate that this immunotherapy is safe and effective in ART-treated animals. Our funded STTR Fast Track grant proposed to investigate a similar therapeutic approach in chronically infected non-ART suppressed individuals. In phase I studies, we will modify our original CAR/CXCR5 DNA construct to confer optimized (opt)CAR/CXCR5-T cells with greater persistence, higher anti-viral binding affinity, and resistance to SIV/HIV infection. In Phase II, we will develop a GMP-scalable method to produce human optCAR/CXCR5-T cells for the first-in-human Phase 1 clinical trial, and this method will be used to produce rhesus macaques optCAR/CXCR5-T cells for use in an IND-enabling preclinical study. The IND-enabling study will assess the safety and efficacy of optCAR/CXCR5-T cells in an SIV model of chronic HIV infection. Here, we are proposing to participate in the I-Corp program with a team consisting of: 1) C-level Corporate Officer, Dr. Athanasiou; 2) Scientific Technical Expert, Dr. Sen; and (3) Industry Expert, Janet White. The team will be led by Maria Athanasiou, PhD, co-founder and CEO of MarPam and Principal Investigator on the Parent Award. Dr. Athanasiou has expertise in drug development, having led a team that developed an FDA approved drug for the treatment of depression, managed a $100 M budget, and provided key contributions to market research and marketing activities. Nandini Sen, PhD, Senior Scientist at MarPam, will participate as a technical expert. Having joined MarPam after working as a Senior Scientist at Stanford University, Dr. Sen brings her vast experience gained over a decade working in the laboratory of Dr. Ann Arvin, a renowned infectious disease expert at Stanford. Rounding out the team, Janet White is a seasoned executive and industry expert with over 35 years of experience in international life science companies. In addition to her proven track record for developing and implementing growth strategies and product development, she is a business adviser to entrepreneurs and early-stage companies through accelerator and mentoring programs. All team members are willing to commit at least 20 hours per week for the duration of the program and have a sincere desire to investigate the commercial landscape surrounding the innovation. This team and the company will benefit immensely from the I-Corps program and the MarPam C-level Corporate Officers are committed to incorporate the learnings from this market research to revise its commercialization strategy.