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: 10039429
• 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/10039429
• 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 Model; Xenograft procedure; acute myeloid leukemia cell; antigen binding; base; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; comorbidity; conditioning; cytokine; design and construction; 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; 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细胞疗法是一种新形式的细胞免疫疗法，其中嵌合抗原受体（CAR）T细胞疗法是一种新的细胞免疫疗法。 使用合成受体重定向T细胞的抗原特异性。CD 19-CAR T细胞已经实现了完全的 高达90%的急性淋巴细胞白血病患者的缓解率。然而，许多恶性肿瘤却不然 具有单一的、高度表达的肿瘤相关抗原（TAA），如CD 19。此外，CD 19阴性 CD 19-CAR T细胞治疗后经常出现复发，这表明多抗原- 需要采取有针对性的办法，以减少复发。急性髓细胞白血病（AML）是最常见的 成人急性白血病和大多数患者将死于他们的疾病。我们和其他人正在评估 CAR T细胞治疗AML然而，AML表现出TAA的异质性表达，其中许多TAA 在造血祖细胞（HPC）上表达，增加了抗原阴性AML免疫反应的风险。 分别在AML靶向CAR T细胞治疗后的逃逸和骨髓毒性。此外，AML 它采用了许多可以抑制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的病毒共转导和分选技术， 系统，以允许产生和纯化具有多个转基因的T细胞，如多个汽车、免疫- 刺激分子、安全开关和分泌的细胞因子。初步数据显示，多功能 CAR T细胞可以被工程化以克服抗原阴性白血病逃逸和免疫抑制 机制等我假设这种新的分选系统可以用来设计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细胞被工程化以克服AML- 还将评价诱导的免疫抑制。在目标2中，目标是针对一组由下式表示的TAA AML和HPC作为移植前CAR T细胞免疫治疗策略的一部分。 在获奖期间，候选人将在纪念斯隆凯特琳癌症中心进行研究 在Marcel货车den Brink博士和一个咨询委员会的指导下。他将获得关键技能， 需要成为一个终身制的物理学家，科学家，经营自己的学术实验室， 生物学方法来改善细胞疗法，并成功地竞争独立的NIH资金。他 将培养一个详细和全面的技能，为同基因，异种移植和人源化小鼠模型， 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 熟练掌握基因组分析，以更好地定义T细胞活化和耗竭状态，并识别 基因治疗的新靶点。