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

一种新型 CAR-T 细胞疗法，用于一次性治疗未接受 ART 抑制的慢性 HIV 感染患者

• 批准号: 10739333
• 负责人: Maria Constance Athanasiou
• 金额: $ 5.5万
• 依托单位: MARPAM PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-22 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10739333
• 关键词: Acceleration; Affinity; Animals; Arvin; Autologous; Award; B-Lymphocytes; BLR1 gene; Binding; Biological Sciences; Biomedical Research; Budgets; Businesses; CAR T cell therapy; CD8-Positive T-Lymphocytes; Cells; Chronic; Communicable Diseases; Cytotoxic T-Lymphocytes; DNA; Devices; Disease remission; Doctor of Philosophy; FDA approved; Funding; Grant; Growth; HIV; HIV Infections; Homing; Hour; Human; Immune; Immunotherapy; Individual; Industry; Innovation Corps; International; Laboratories; Learning; Macaca mulatta; Market Research; Marketing; Mental Depression; Mentors; Methods; Modeling; Parents; Patients; Pharmacotherapy; Phase; Phase I Clinical Trials; Pilot Projects; Primates; Principal Investigator; Resistance; SIV; Seasons; Senior Scientist; Site; Small Business Technology Transfer Research; Study models; T-Lymphocyte; Therapeutic; Translations; Universities; Viral; Virus; Virus Replication; antiretroviral therapy; chimeric antigen receptor; chimeric antigen receptor T cells; commercialization; drug development; experience; first-in-human; innovation; member; novel; phase 1 study; pre-clinical; preclinical study; product development; programs; safety assessment; targeted treatment

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.

摘要 基于我们成功的灵长类动物模型研究，我们的目标是开发一种持久缓解的一次性治疗方法 人类免疫缺陷病毒（HIV）在没有抗逆转录病毒治疗（ART）。这种有针对性的治疗 是一种自体HIV特异性嵌合抗原受体（CAR）-T细胞疗法， 这种“装置”可以将抗病毒杀伤T细胞引导到B细胞滤泡中，在那里它们可以消除产生病毒的细胞。B细胞 滤泡是一个“隐藏的”免疫保护位点，由于病毒特异性CD 8水平低， T细胞。我们在猴免疫缺陷病毒（SIV）感染的恒河猴中进行的临床前CAR/CXCR 5-T细胞初步研究 HIV的猕猴模型的研究表明，这种免疫疗法在ART治疗的动物中是安全和有效的。我们 资助的STTR快速通道赠款建议在慢性感染中研究类似的治疗方法， 非抗逆转录病毒疗法抑制的个体。在I期研究中，我们将修改我们原始的CAR/CXCR 5 DNA构建体， 赋予优化的（opt）CAR/CXCR 5-T细胞更大的持久性、更高的抗病毒结合亲和力，以及 抗SIV/HIV感染。在第二阶段，我们将开发一种GMP可扩展的方法， optCAR/CXCR 5-T细胞用于首次人体1期临床试验，该方法将用于生产 恒河猴optCAR/CXCR 5-T细胞用于IND使能临床前研究。IND赋能研究 将评估optCAR/CXCR 5-T细胞在慢性HIV感染的SIV模型中的安全性和有效性。在这里， 我们建议参加I-Corp计划的团队包括：1）C级公司官员， 博士Athanasiou; 2）科学技术专家，Sen博士;和（3）行业专家，Janet白色。该小组将 由MarPam的联合创始人兼首席执行官Maria Athanasiou博士领导，并担任父母奖的首席研究员。 博士Athanasiou在药物开发方面具有专业知识，他领导的团队开发了FDA批准的药物 用于治疗抑郁症，管理着1亿美元的预算，并为市场研究做出了重要贡献 和营销活动。MarPam高级科学家Nandini Sen博士将作为技术专家参加。 Sen博士在斯坦福大学担任高级科学家后加入MarPam， 在Ann阿尔文博士的实验室工作了十多年， 斯坦福大学的专家。珍妮特·白色（Janet White）是团队的组成部分，她是一位经验丰富的高管和行业专家，拥有超过 在国际生命科学公司拥有35年的经验。除了她的良好记录， 制定和实施增长战略和产品开发，她是一个商业顾问， 通过加速器和指导计划为企业家和早期公司提供支持。所有团队成员都是 愿意承诺每周至少20小时的计划期间，并有真诚的愿望， 调查围绕创新的商业前景。这支球队和公司都将受益 来自I-Corps计划和MarPam C级公司官员的大量人员致力于将 从这次市场调查中学习，以修改其商业化战略。