权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Modulation of repopulation of anti HIV-1 gene-modified cells to enhance efficacy and safety

调节抗 HIV-1 基因修饰细胞的再增殖以提高功效和安全性

基本信息

批准号：
10614651
负责人：
Dong Sung An
金额：
$ 45.36万
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：
2020
资助国家：
美国
起止时间：
2020-05-07 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614651
关键词：
Adverse effects Antigens Autoimmune B-Lymphocytes Benefits and Risks Bone Marrow Purging CAR T cell therapy CD19 gene Cell Count Cell surface Cells Cellular Immunity Cetuximab Clinical Clinical Trials Collaborations Combined Modality Therapy Comparative Study Dangerousness Disease Effector Cell Engineered Gene Engraftment Epidermal Growth Factor Receptor Erbitux FDA approved Gene Delivery Gene Modified Genetic Engineering Goals HIV HIV-1 Hematopoietic stem cells Human Humoral Immunities Hypoxanthine Phosphoribosyltransferase Immune In Vitro Investigational New Drug Application Learning Lentivirus Vector MGMT gene Macaca nemestrina Malignant - descriptor Malignant Neoplasms Methotrexate Modeling Mus Patients Population Procedures Prodrugs RNA Interference Reaction Safety T-Lymphocyte Testing Therapeutic Thioguanine Toxic effect Transplantation Treatment Efficacy Virus Replication cancer immunotherapy chimeric antigen receptor chimeric antigen receptor T cells clinically relevant cytokine release syndrome gene therapy immunoengineering immunogenicity in vivo knock-down mutant neutralizing antibody nonhuman primate preclinical development programs timeline

项目摘要

Project 3: Summary/Abstract The overall goal of Project 3 is to modulate the levels of anti-HIV-1 chimeric antigen receptor (CAR) and broadly neutralizing antibodies (bNAb) modified immune cells by developing the most effective and safe positive and negative selection strategy to (1) achieve a therapeutic level of repopulation and (2) incorporate a safety “kill-switch” to eliminate the genetically engineered anti-HIV-1 immune effector cells in cases of unexpected adverse effects, such as cytokine storm, autoimmune reaction and malignant transformation. The hematopoietic stem cell-based gene therapy approach has shown great promise to achieve an HIV-1 cure. However, one of the major limitations has been the difficulty of achieving the engraftment levels sufficient to provide therapeutic efficacy, in particular for HIV-1 infected patients where intensive myeloablative conditionings would be an unfavorable risk-benefit. Thus, a safe and titratable positive selection strategy is highly desirable to maximize the level of anti-HIV-1 gene engineered immune cells to treat patients with HIV-1 without dangerous intensive myeloablation. Furthermore, it is important to incorporate a safety “kill-switch” procedure to eliminate the genetically engineered anti-HIV-1 immune effector cells based on lessons learned from severe adverse effects in cancer immunotherapy. Therefore, we will develop a negative selection strategy as a safety “kill-switch” to eliminate genetically engineered immune cells. We will identify the most effective and safe selection strategy from (1) knocking down hypoxanthine-guanine phosphoribosyltransferase (HPRT) expression using RNA interference that enables us to effectively enrich or eliminate anti-HIV-1 gene-modified HSPC using clinically available prodrug 6-thioguanine or methotrexate, (2) co-expressing truncated non-functional human epidermal growth factor receptor (huEGFRt), a cell surface marker for a rapid ex vivo positive selection and in vivo negative selection by an FDA-approved anti-EGFR monoclonal antibody Cetuximab (Erbitux) and (3) the P140K mutant form of human O6-methylguanine-DNA-methyltransferase (MGMTP140K) for a positive selection. We hypothesize that a clinically relevant, safe and effective positive and negative selection strategy can be developed by rigorously evaluating our proposed selection strategies for our anti-HIV-1 CAR and scFv-Fc bNAb combining therapies to achieve a cure of HIV disease.

项目3：摘要/摘要