CAR T CELLS ENGINEERED TO KILL HIV-INFECTED CELLS WHILE SECRETING BROADLY NEUTRALIZING ANTIBODIES

CAR T 细胞旨在杀死 HIV 感染细胞，同时分泌广泛中和抗体

• 批准号: 10580004
• 负责人: Brian Lawson
• 金额: $ 48万
• 依托单位: SCINTILLON INSTITUTE FOR PHOTOBIOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-25 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580004
• 关键词: Address; Adverse event; Affinity; Anti-Retroviral Agents; Antibodies; Antigens; Autologous; Binding; Binding Sites; Biological Assay; CD8-Positive T-Lymphocytes; Cell Line; Cells; Chemicals; Chronic; Disease Progression; Evaluation; Future; Generations; Goals; HIV; HIV Infections; Human; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Link; Membrane; Methods; Modality; Modeling; Mus; Nature; Patients; Process; Productivity; Proviruses; Route; Scanning; Serum; Signal Transduction; Surface; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Viral; Viral Load result; Viral Proteins; Viral reservoir; Virus; Virus Latency; antiretroviral therapy; cell killing; cellular transduction; chimeric antigen receptor; chimeric antigen receptor T cells; combat; design; engineered T cells; humanized mouse; improved; in vivo; in vivo evaluation; innovation; insight; latent HIV reservoir; mouse model; neutralizing antibody; nonhuman primate; novel; novel strategies; pathogen; prophylactic; simian human immunodeficiency virus; synergism; vector; virtual

PROJECT SUMMARY A cure for HIV requires the elimination of the latently-infected pool of host cells harboring HIV provirus, but this has proven quite difficult and remains a major obstacle in the field. Currently, several chemical latency reversing agents have been described, however, their in vivo efficacy has not been demonstrated. Thus, the need for new approaches to address this issue is urgently needed. One attractive method to combat HIV latency, would be a self-sustaining curative to endlessly surveil the host rapidly killing newly activated reservoir cells before the release of a significant amount of virus. Previously, T cells transduced to express CD4 on their surface linked to activation signaling machinery, chimeric antigen receptor (CAR) T cells, were employed to target and kill infected host cells. But there were substantial drawbacks with this approach, including a novel entry route for infection of CD8 T cells, shielding of the CD4-binding site, and lack of efficacy. Utilizing secreted high-affinity anti-HIV bnAbs, which are remarkably effective across a wide swath of HIV strains, in conjunction with superior CAR designs, we here propose to exploit both advancements to generate doubly immunotherapeutic improved CAR T cells. These pioneering studies will provide new insights into how to access and control the reservoir of latently HIV-infected cells and, in combination with ART, address the exigent goal of functional control of HIV. Upon completion of this project, we expect to have several validated CAR T cell constructs ready for future testing in SHIV non-human primate models and/or perhaps humans. Since these studies utilize autologous T cells, we expect to see very few adverse events. Moreover, if successful, life-long use of anti-retrovirals, which have been associated with toxicity, is likely to be reduced or perhaps eliminated by this approach.

项目概要 治愈艾滋病毒需要消除携带艾滋病毒原病毒的潜伏感染宿主细胞库， 但事实证明这相当困难，并且仍然是该领域的主要障碍。目前，几种化学潜伏期 逆转剂已被描述，然而，其体内功效尚未得到证实。因此， 迫切需要采取新方法来解决这一问题。一种对抗艾滋病毒的有吸引力的方法 潜伏期，将是一种自我维持的治疗方法，可以无休止地监视宿主，迅速杀死新激活的储存库 细胞在释放大量病毒之前。此前，T 细胞被转导以表达 CD4 表面连接到激活信号机制，嵌合抗原受体（CAR）T细胞，被用来 靶向并杀死受感染的宿主细胞。但这种方法有很大的缺点，包括新颖的 CD8 T 细胞感染的进入途径、CD4 结合位点的屏蔽以及缺乏功效。利用分泌的 高亲和力抗 HIV bnAb，在广泛的 HIV 毒株中非常有效，结合 凭借卓越的 CAR 设计，我们在此建议利用这两项进步来产生双倍的 免疫治疗改良的 CAR T 细胞。这些开创性的研究将为如何 进入并控制潜在 HIV 感染细胞的储存库，并与 ART 相结合，解决 HIV功能控制的迫切目标。该项目完成后，我们预计会有一些经过验证的 CAR T 细胞构建体已准备好用于未来在 SHIV 非人类灵长类动物模型和/或人类中进行测试。 由于这些研究使用自体 T 细胞，因此我们预计很少会出现不良事件。此外，如果 成功地、终生使用抗逆转录病毒药物可能会减少或减少毒性，因为抗逆转录病毒药物与毒性有关。 也许通过这种方法消除了。