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：
10160822
负责人：
Dong Sung An
金额：
$ 46.67万
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/10160822
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 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 Lentivirus Vector MGMT gene Macaca nemestrina Malignant - descriptor Malignant Neoplasms Methotrexate Modeling Mus Patients Procedures Prodrugs RNA Interference Reaction Risk Safety T-Lymphocyte Testing Therapeutic Thioguanine TimeLine Toxic effect Transplantation Treatment Efficacy Virus Replication base 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

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/摘要项目3的总体目标是通过制定最有效，最安全和负面的选择策略（1）实现治疗水平的重生水平，并在疾病中，（2）在疾病中，（2）在疾病中融合了杀戮性的altive，抗杀伤性仇敌，通过开发最有效和安全的阳性和负面选择策略来调节抗HIV-1嵌合抗原受体（CAR）和广泛中和抗体（BNAB）修改的免疫电池的水平。例如细胞因子风暴，自身免疫反应和恶性转化。造血干细胞基因疗法方法表现出了实现HIV-1治疗的巨大希望。但是，主要局限性之一是难以达到足以提供治疗效率的植入水平，尤其是对于HIV-1感染的患者而言，密集的骨髓性疾病将是一种不利的风险效益。那是一个安全且钛平均值的正面。选择策略是非常需要的，可以最大程度地提高抗HIV-1基因工程免疫球的水平，以治疗HIV-1患者而无需危险的密集骨髓。此外，重要的是要根据从癌症免疫疗法中严重的不良反应中学到的经验教训来消除一般设计的抗HIV-1免疫球效应细胞，这一点很重要。因此，我们将制定一种负面选择策略作为安全的“杀戮开关”，以消除基因工程的免疫核管。我们将使用RNA干扰来确定（1）从（1）中确定（1）敲击低黄嘌呤甘氨酸磷酸糖基转移酶（HPRT）表达的表达 (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.我们假设，可以通过严格评估我们针对抗HIV-1 CAR和SCFV-FC BNAB结合疗法以实现HIV疾病的疗法，可以通过严格评估我们提出的选择策略来制定临床相关，安全和有效的选择策略。