Multi-antigen-specific CAR T cells to treat acute myeloid leukemia

多抗原特异性 CAR T 细胞治疗急性髓系白血病

基本信息

批准号：
10472541
负责人：
Scott E James
金额：
$ 26.3万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10472541
关键词：
Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Adult Advisory Committees Age Allogenic Antigen Targeting Antigens Autologous Award Bone Marrow Bone Marrow Cells Bone Marrow Purging CAR T cell therapy CD 200 CD19 gene CD3 Antigens CD69 antigen CRISPR/Cas technology Cell Therapy Cell model Cells Cellular immunotherapy Chemotherapy and/or radiation Clinical Complication Data Detection Diagnosis Disease Engineering Engraftment Exhibits Funding Gene-Modified Generations Genes Genomics Goals Granzyme Hematopoietic Hematopoietic stem cells Heterogeneity Immune Immune Evasion Immune System Diseases Immune response Immuno-Chemotherapy Immunosuppression Immunotherapy In complete remission Interleukin-12 Laboratories Legal patent Leucine Zippers Leukemic Cell Malignant Neoplasms Mediating Memorial Sloan-Kettering Cancer Center Mentorship Molecular Myelogenous Myeloid-derived suppressor cells Names Patients Physicians Process Progenitor Cell Engraftment Proteins Recurrent disease Regimen Regulatory T-Lymphocyte Relapse Research Resistance Risk Running Safety Scientist Signal Transduction Site Sorting - Cell Movement Specificity System T-Cell Activation T-Lymphocyte Technology Toxic effect Transforming Growth Factor beta Transgenes Translations Transplantation Tumor Antigens United States National Institutes of Health Viral Viral Vector Xenograft procedure acute myeloid leukemia cell antigen binding base chemotherapy chimeric antigen receptor chimeric antigen receptor T cells comorbidity conditioning cytokine design and construction efficacious treatment engineered T cells exhaustion gene therapy graft vs host disease hematopoietic cell transplantation humanized mouse immune checkpoint improved interleukin-12 receptor knowledge base leukemia novel novel therapeutics patient derived xenograft model perforin prevent programmed cell death ligand 1 receptor recruit skills success synthetic biology tenure track

项目摘要

PROJECT SUMMARY Chimeric antigen receptor (CAR) T cell therapy is a novel form of cellular immunotherapy in which the antigen specificity of T cells is redirected using synthetic receptors. CD19-CAR T cells have achieved complete responses in up to 90% of patients with acute lymphoblastic leukemia. However, many malignancies do not possess a single, highly expressed tumor-associated antigen (TAA) such as CD19. Furthermore, CD19-negative relapses have been frequently encountered following CD19-CAR T cell therapy, suggesting that multi-antigen- targeting approaches will be needed to reduce relapse. Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the majority of patients will die from their disease. We and others are evaluating CAR T cells to treat AML. However, AML exhibits heterogeneous expression of TAAs and many of these TAAs are expressed on hematopoietic progenitor cells (HPCs), increasing the risk of antigen-negative AML immune escape and bone marrow toxicity following AML-targeting CAR T cell therapy, respectively. Additionally, AML employs many active immune-suppressive strategies that may inhibit CAR T cells. To overcome these challenges, I have recently developed a novel viral co-transduction and sorting system to allow generation and purification of T cells with multiple transgenes such as multiple CARs, immune- stimulating molecules, safety switches, and secreted cytokines. Preliminary data suggest that multi-functional CAR T cells can be engineered to overcome antigen-negative leukemia escape and immune suppression mechanisms. I hypothesize that this novel sorting system can be used to engineer T cells to overcome AML TAA heterogeneity and immune suppressive strategies. Aim 1 will investigate CAR T cells simultaneously targeting a set of AML TAAs and predicted to avoid toxicity to HPCs. CAR T cells engineered to overcome AML- induced immune suppression will also be evaluated. In Aim 2 the goal is to target a set of TAAs expressed by both AML and HPCs as part of a pre-transplant CAR T cell immunotherapy strategy. During the award period, the candidate will conduct research at Memorial Sloan Kettering Cancer Center under the mentorship of Dr. Marcel van den Brink and an Advisory Committee. He will obtain the critical skills he needs to become a tenure-track physician-scientist running his own academic laboratory developing synthetic biology approaches to improve cellular therapies and successfully competing for independent NIH funding. He will cultivate a detailed and comprehensive skill set for syngeneic, xenograft, and humanized mouse models of cellular immunotherapy, build upon an existing knowledge base of molecular construct design and cellular gene modification by mastering multiplexed CRISPR/Cas9 gene disruptions and site-specific gene integration, and develop proficiency in genomic analysis to better define T cell activation and exhaustion states and to identify novel targets for gene therapy.

项目概要嵌合抗原受体（CAR）T细胞疗法是一种新型的细胞免疫疗法，其中 T 细胞的抗原特异性通过合成受体进行重定向。 CD19-CAR T细胞已实现完全高达 90% 的急性淋巴细胞白血病患者有缓解。然而，许多恶性肿瘤并不具有单一、高表达的肿瘤相关抗原（TAA），例如 CD19。此外，CD19阴性 CD19-CAR T 细胞治疗后经常遇到复发，这表明多抗原需要采取针对性方法来减少复发。急性髓系白血病 (AML) 是最常见的成人急性白血病，大多数患者会死于该病。我们和其他人正在评估 CAR T 细胞治疗 AML。然而，AML 表现出 TAA 的异质表达，其中许多 TAA 在造血祖细胞 (HPC) 上表达，增加抗原阴性 AML 免疫的风险分别是针对 AML 的 CAR T 细胞治疗后的逃逸和骨髓毒性。此外，反洗钱采用许多可能抑制 CAR T 细胞的主动免疫抑制策略。为了克服这些挑战，我最近开发了一种新型病毒共转导和分选系统允许生成和纯化具有多个转基因的 T 细胞，例如多个 CAR、免疫- 刺激分子、安全开关和分泌的细胞因子。初步数据表明，多功能 CAR T 细胞可被改造以克服抗原阴性白血病逃逸和免疫抑制机制。我假设这种新颖的分选系统可用于改造 T 细胞以克服 AML TAA 异质性和免疫抑制策略。目标 1 将同时研究 CAR T 细胞针对一组 AML TAA，预计可避免对 HPC 产生毒性。 CAR T 细胞被设计用于克服 AML- 还将评估诱导的免疫抑制。在目标 2 中，目标是针对一组 TAA，其表示为 AML 和 HPC 都是移植前 CAR T 细胞免疫治疗策略的一部分。获奖期间，候选人将在纪念斯隆凯特琳癌症中心进行研究在 Marcel van den Brink 博士和咨询委员会的指导下。他将获得他所掌握的关键技能需要成为一名终身教授医师科学家，经营自己的学术实验室，开发合成药物生物学方法改善细胞疗法并成功竞争独立的 NIH 资金。他将为同基因、异种移植和人源化小鼠模型培养详细而全面的技能细胞免疫疗法，建立在分子构建设计和细胞基因的现有知识基础之上通过掌握多重 CRISPR/Cas9 基因破坏和位点特异性基因整合进行修饰，以及提高基因组分析的熟练程度，以更好地定义 T 细胞激活和耗竭状态并识别基因治疗的新靶点。