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

• 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
• 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

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.

项目摘要 嵌合抗原受体（CAR）T细胞疗法是一种新型的细胞免疫疗法形式，其中 使用合成受体重定向T细胞的抗原特异性。 CD19卡车T细胞已完成 多达90％的急性淋巴细胞白血病患者的反应。但是，许多恶性肿瘤没有 拥有一个高度表达的肿瘤相关抗原（TAA），例如CD19。此外，CD19阴性 CD19卡尔T细胞疗法经常遇到复发，这表明多抗原 - 需要定位方法来减少复发。急性髓样白血病（AML）是最常见的 成人和大多数患者的急性白血病将死于疾病。我们和其他人正在评估 CAR T细胞治疗AML。但是，AML表现出TAA和许多TAA的异质表达 在造血祖细胞（HPC）上表达，增加了抗原阴性AML免疫的风险 逃脱和骨髓毒性分别在靶向AML的CAR T细胞疗法后。另外，AML 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的病毒式共同塑料和分类 允许用多个转基因（例如多个汽车）产生和纯化T细胞的系统 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 可以设计CAR T细胞以克服抗原阴性白血病逃脱和免疫抑制 机制。我假设这个新颖的分选系统可用于设计T细胞来克服AML TAA异质性和免疫抑制策略。 AIM 1将同时研究汽车T细胞 针对一组AML TAA，并预测避免对HPC的毒性。旨在克服AML-的CAR T细胞 还将评估诱导的免疫抑制。在AIM 2中，目标是针对一组由 AML和HPC作为移植前CAR T细胞免疫疗法策略的一部分。 在奖励期间，候选人将在纪念斯隆·克特林癌症中心进行研究 在Marcel Van Den Brink博士的指导下和咨询委员会的指导下。他将获得他的关键技能 需要成为持有自己的学术实验室发展合成的终身制医师科学家 生物学方法可以改善细胞疗法并成功争夺独立的NIH资金。他 将培养用于合成性，异种移植物和人源化的小鼠模型的详细而全面的技能 细胞免疫疗法，建立在分子构造设计和细胞基因的现有知识基础上 通过掌握多重CRISPR/CAS9基因中断和特定地点基因整合的修改，并 提高基因组分析的熟练程度，以更好地定义T细胞激活和衰竭状态并确定 基因疗法的新靶标。