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Gene-engineered stem cell memory T-cells with anti-HIV chimeric antigen receptors

具有抗 HIV 嵌合抗原受体的基因工程干细胞记忆 T 细胞

基本信息

批准号：
9317405
负责人：
Masakazu Kamata
金额：
$ 38.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-18 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317405
关键词：
Acquired Immunodeficiency Syndrome Acute Adoptive Immunotherapy Adoptive Transfer Antigens Autologous B-Cell Leukemia B-Cell Lymphomas Bone Marrow CD19 Antigens CD19 gene CD28 gene CD4 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Aging Cell physiology Cells Chronic Chronic Lymphocytic Leukemia Clinical Clinical Trials Cytotoxic T-Lymphocytes Disease Engineered Gene Engineering Ensure Extracellular Domain Failure Gene-Modified Genes Goals HIV HIV Antibodies HIV Infections HIV-1 HLA Antigens Helper-Inducer T-Lymphocyte Histocompatibility Antigens Class II Human Immune Immune response Immunity Immunotherapeutic agent Immunotherapy In Vitro Individual Infection Interleukin-16 Lead Ligands Link Liver Mediating Memory Modeling Mus Mutation Patients Persons Phenotype Predisposition Prevention Property Public Health Reporting Research Signal Transduction Source Specificity Stem cells Supplementation System T memory cell T-Cell Receptor T-Lymphocyte Technology Testing Thymus Gland Transplant Recipients Transplantation Viral Viral Load result Viremia Virus antiretroviral therapy base cancer clinical trial cellular engineering cellular transduction chimeric antigen receptor clinical practice cytotoxicity design exhaustion human disease in vitro activity in vitro testing in vivo in vivo Model leukemia/lymphoma mouse model neutralizing antibody novel novel strategies prevent receptor response self renewing cell self-renewal stemness tool vector

项目摘要

PROJECT SUMMARY CD8+ cytotoxic T-lymphocytes (CTLs) transiently control HIV in infected persons, but eventually fail due to viral mutation and other factors, resulting in persistent or chronic infection. However, reports of CTLs suppressing HIV infection in a few patients indicate that overcoming these barriers would allow for successful CTL-mediated control of HIV infection. Adoptive immunotherapy strategies aim to confer directed and enhanced CTL responses via supplementation of ex vivo-expanded autologous CD8+ T cells expressing a desired antigen-specific T cell receptor (TCR). However, these cells are mostly dysfunctional due to decreased proliferative response and limited CTL activity. Moreover, the requirement for a particular human-leukocyte antigen to properly present antigen to the T cell limits exogenous TCR-based approaches. Thus, such approaches have had minimal effects on reducing HIV-viral load. Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity onto immune effector T cells. In recent years, CAR immunotherapies have been extensively promoted in anti-cancer clinical trials. Of these, adoptively transferred autologous T cells modified with anti-CD19 CAR showed a dramatic impact on B cell lymphomas in acute and chronic lymphocytic leukemia patients. We hypothesize that CAR immunotherapy against HIV-infected cells can eradicate persistently infected cells and HIV latent reservoirs in patients following reactivation. Regarding an anti-HIV CAR, CD4ζ CAR consisting of the extracellular domain of the human CD4 molecule linked to the CD3ζ-chain has been well-studied in vitro and in human clinical trials. This CAR has been shown to mediate highly potent anti-HIV activity in vitro, but had limited effects due to poor survival and functionality of the transduced cells. We considered potential reasons for this failure due to 1) susceptibility of CD4+ T cells and CD8+ T cells expressing CD4ζ CAR to HIV infection, 2) lack of costimulatory signaling domains required for proper effector and memory response, and 3) massive ex vivo expansion of T cells prior to gene modification leading to cellular aging, resulting in poor effector and memory function. Our overall goal is to confer long-term, enhanced HIV-specific effector and memory responses via transplantation of anti-HIV CAR-engineered T cells. We will 1) develop a new class of anti-HIV CAR using HIV- targeting broadly neutralizing antibodies, 2) protect CAR-transduced T cells from HIV-mediated cytotoxicity by co- transduction with anti-HIV genes, 3) introduce costimulatory-signaling domains into anti-HIV CAR to ensure superior effector and memory responses, and 4) use newly identified memory T cells retaining stem cell properties called “stem cell memory T (TSCM) cells” as a carrier vehicle for anti-HIV CAR. TSCM cells self-renew in vitro as well as in vivo and differentiate into effector T cells. Thus, TSCM cells engineered to express HIV-specific CAR provide an inexhaustible source of HIV-specific immune cells. These studies will be further modeled in vivo using the humanized bone marrow, liver and thymus (BLT) mouse system.

项目摘要 CD 8+细胞毒性T淋巴细胞（CTL）暂时控制感染者中的HIV，但最终由于病毒感染而失败。突变和其他因素，导致持续或慢性感染。然而，关于CTL抑制HIV的报道少数患者感染表明，克服这些障碍将允许成功的CTL介导的控制艾滋病毒感染。连续性免疫治疗策略旨在通过以下途径赋予定向和增强的CTL应答：补充表达所需抗原特异性T细胞的离体扩增的自体CD 8 + T细胞受体（TCR）。然而，这些细胞由于增殖反应降低和有限的增殖能力而大多功能失调。 CTL活性。此外，需要特定的人白细胞抗原来适当地将抗原呈递给 T细胞限制了基于外源性TCR的方法。因此，这些方法对减少 HIV病毒载量嵌合抗原受体（汽车）是人工工程化的受体，其赋予嵌合抗原受体（CAR）所需的特异性。免疫效应T细胞。近年来，CAR免疫疗法在抗癌中得到了广泛推广。临床试验其中，用抗CD 19 CAR修饰的过继转移的自体T细胞显示出显著的免疫应答。对急性和慢性淋巴细胞白血病患者B细胞淋巴瘤影响。我们假设CAR 针对HIV感染细胞的免疫疗法可以根除持续感染的细胞和HIV潜伏库，患者恢复活动后。关于抗HIV CAR，由CD 4 + CAR的胞外结构域组成的CD 4 + CAR，与CD 3 β-链连接的人CD 4分子已经在体外和人体临床试验中得到充分研究。这 CAR已被证明在体外介导高度有效的抗HIV活性，但由于存活率低而效果有限和功能性。我们考虑了该失败的潜在原因，原因如下：1） CD 4 + T细胞和CD 8 + T细胞表达抗HIV感染的CD 4 β CAR，2）缺乏共刺激信号传导结构域适当的效应子和记忆应答所需，和3）在基因转移之前T细胞的大量离体扩增，修饰导致细胞老化，导致效应子和记忆功能差。我们的总体目标是通过以下途径赋予长期增强的HIV特异性效应子和记忆反应：抗HIV CAR工程化T细胞的移植。我们将1）开发一种新的抗HIV CAR，靶向广泛中和抗体，2）通过共- 3）将共刺激信号传导结构域引入抗HIV CAR中以确保上级效应器和记忆反应，以及4）使用新鉴定的保留干细胞特性的记忆T细胞称为“干细胞记忆T（TSCM）细胞”作为抗HIV CAR的载体。TSCM细胞在体外也能自我更新并分化成效应T细胞。因此，经工程化以表达HIV特异性CAR的TSCM细胞提供了一种取之不尽的HIV特异性免疫细胞来源。这些研究将进一步在体内建模，使用人源化骨髓、肝脏和胸腺（BLT）小鼠系统。