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Development of Allogeneic CAR T Cell Therapy for a Functional Cure of HIV Infection

开发同种异体 CAR T 细胞疗法以功能性治愈 HIV 感染

基本信息

批准号：
10480991
负责人：
TODD M ALLEN
金额：
$ 48.86万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10480991
关键词：
Address Allogenic Anti-Retroviral Agents Autologous B-Cell Acute Lymphoblastic Leukemia Berlin CAR T cell therapy CCR5 gene CD19 gene CD28 gene CD8-Positive T-Lymphocytes Cardiovascular Diseases Cells Cellular biology Cellular immunotherapy Characteristics Chronic Clinical Clinical Trials Consumption Cytomegalovirus DNA Data Development Disease Disease Progression Disease remission Exhibits Functional disorder Generations Genes Genetic HIV HIV Infections HIV vaccine Head Hematopoietic Neoplasms Heterogeneity Human Immune Immune response Immune system Immunotherapeutic agent Immunotherapy Individual Infection Inflammation Infusion procedures Interruption Junk DNA Knowledge Life London Macaca mulatta Malignant Neoplasms Mediating Modification Morbidity - disease rate Pathogenesis Pathogenicity Patients Pharmaceutical Preparations Phenotype Production Resistance SIV Source T cell response T-Cell Development T-Lymphocyte Testing Therapeutic Time Tissues Vaccination Variant Viral Viral Load result Viral reservoir Virus allotransplant anti-viral efficacy antiretroviral therapy base base editing cancer immunotherapy chimeric antigen receptor chimeric antigen receptor T cells chronic infection cost efficacy study engineered T cells human disease humanized mouse improved in vivo interest mortality mouse model novel prevent prophylactic response stem cells success transcriptomics tumor vector-based vaccine vector-induced viral rebound

项目摘要

Abstract: Antiretroviral therapy (ART) dramatically reduces HIV-associated morbidity and mortality (1). However, it is not a practical cure as eradication of HIV through ART alone is estimated to require over 60 years of treatment (1, 2). Numerous studies support that HIV-specific T cell responses are critical for efficient targeting and elimination of HIV infected cells that are the source of chronic infection (3-10). Unfortunately, viral escape and a limited presence of functional virus-specific effector CD8+ T cells undermine the potency of these responses in chronically infected individuals (11-17). As such, there is growing interest in the development of novel immunotherapeutic approaches to target and eliminate HIV-infected cells to achieve viral suppression in the absence of ART, a “functional cure”. Chimeric antigen receptor (CAR) T cell immunotherapies have demonstrated great promise against blood cancers (18-20), and now also demonstrate the potential to mitigate HIV/SIV infection in rhesus macaques (21, 22) and humanized mice (23-28). We recently showed that HIV-specific Dual CD4-based CAR T cells co- expressing independent 4-1BB and CD28 costimulatory domains restrict HIV replication and reduce viral burden in humanized mice (23). However, current limitations of using autologous T cells to derive CAR T cell products (TCPs), including time-consuming and costly manufacturing, insufficient or dysfunctional patient-derived T cells, and the inter-patient heterogeneity of TCPs, are barriers to their widespread application to human diseases. Development of allogeneic TCPs derived from healthy human donors, could, however, provide an ‘off-the-shelf’ treatment option to overcome these hurdles, as well as accelerate the use of CAR T cell therapies (29-38). Unfortunately, post-infusion elimination by the recipient’s immune system remains a major hurdle (39-41). Here we propose to leverage our expertise in CAR T cell biology (21, 23, 25, 26, 42, 43), base editing (44-49), and a humanized mouse model of HIV infection (50-58) to develop an allogeneic CAR T cell therapy against HIV. Building on our preliminary data applying efficient multiplex base editing to CAR T cells, we hypothesize that both base editing approaches and identification of an optimal allogenic donor will enable the development of an allorejection-resistant CD4-based CAR TCP with enhanced efficacy to eliminate HIV-infected cells and suppress HIV in the absence of ART. To test this hypothesis, we propose the following specific aims: Aim 1: Determine whether genetic modifications to allogeneic T cells can augment their in vivo persistence. Aim 2: Identify characteristics of allogeneic HIV-specific CD4CAR T cells that associate with enhanced persistence and antiviral efficacy. Aim 3: Compare the in vivo HIV efficacy of allogeneic versus autologous HIV-specific CD4CAR T cells, incorporating Aim 1 and 2’s signatures of improved allogeneic functionality.

摘要：抗逆转录病毒治疗（ART）可显著降低hiv相关的发病率和死亡率(1)。