Project 2: Towards a safe and effective AML treatment strategy using anti-CD33 CAR T cells in combination with CAR-resistant hematopoietic stem cells

项目2：利用抗CD33 CAR T细胞联合CAR耐药造血干细胞，制定安全有效的AML治疗策略

• 批准号: 10245064
• 负责人: CARL H. JUNE
• 金额: $ 31.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245064
• 关键词: Acute Myelocytic Leukemia; Address; Adoptive Immunotherapy; Allogenic; Antigen Targeting; Antigens; Autologous; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Berlin; Bone Marrow Purging; CAR T cell therapy; CCR5 gene; CD19 gene; CD33 antigen; CD34 gene; CD4 Positive T Lymphocytes; CRISPR/Cas technology; CSF3 gene; Cell Therapy; Cell surface; Cells; Cessation of life; Clinical; Clinical Trials; Cytogenetics; Data; Eligibility Determination; Engineering; Evaluation; Exons; Genes; Genetic Engineering; Goals; HIV; HIV Receptors; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; IL3RA gene; Immunotherapy; In complete remission; Individual; Infusion procedures; Journals; Knock-out; Lead; Lentivirus Vector; Ligands; MS4A1 gene; Malignant Neoplasms; Marrow; Mediating; Medical; Medicine; Messenger RNA; Metabolism; Mission; Monoclonal Antibodies; Mus; Myelogenous; Myeloproliferative disease; Nature; New England; Oncology; Patients; Phenotype; Physicians; Public Health; Publishing; Relapse; Reporting; Research; Resistance; Scientist; Surface; Surface Antigens; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Translating; Transplantation; Work; Xenograft Model; base; cellular transduction; chimeric antigen receptor; chimeric antigen receptor T cells; curative treatments; donor stem cell; engineered T cells; exome sequencing; experimental study; extracellular; feasibility testing; genetically modified cells; in silico; in vivo; innovation; leukemia; monocyte; neutrophil; novel; novel therapeutics; peripheral blood; pre-clinical; preservation; response; risk mitigation; rituximab; safety and feasibility; scale up; side effect; success; trafficking; treatment strategy

SUMMARY/ABSTRACT (PROJECT 2) Immunotherapy has revolutionized the treatment of a variety of advanced malignancies. Anti-CD19 chimeric antigen receptor redirected T cells (CART-19) have been particularly successful in B-cell malignancies. How to translate the success of CART cell therapy to other malignancies such as acute myeloid leukemia (AML) remains an important question in the field. A critical requirement of CART cell therapy is that the target tissue be expendable. AML is a malignancy of the hematopoietic stem/progenitor cells (HSPC) and shares cell surface antigens with normal HSPC and with normal myeloid progeny such as neutrophils and monocytes. It has become clear that the lack of AML-specific antigens is the single biggest impediment to unleashing the power of CART cells against AML and other myeloid malignancies. The long-term goal of this project is to develop a clinically feasible CART cell platform for AML, by creating AML-specific CART cells that are able to expand and persist in vivo to eradicate AML while preserving normal marrow function. The central hypothesis is that a durable anti-leukemic effect from anti-CD33 CART cells can co-exist with adequate levels of genetically engineered CD33-deficient hematopoiesis. This will be accomplished in three specific aims. In Aim 1, high quality depletable anti-CD33 CAR T cells will be manufactured. These will be allogeneic, donor-derived T cells transduced with a biscistronic lentiviral vector that encodes a humanized anti-CD33-41BB-zeta CAR as well as CD20. In Aim 2, the feasibility and safety of manufacturing CD33-deficient human HSPC will be tested and regulatory approvals to manufacture CD33-deficient HSPC will be obtained. In Aim 3, a clinical trial will be conducted of a combined approach incorporating CD33-deficient, CAR-resistant allogeneic HCT followed by CART-33 infusion in patients with AML. This research will be significant because it will contribute depth (of clinical responses) and breadth (of eligibility for potentially curative therapy) to the therapeutic arsenal against AML. The innovation of the proposed research lies in replacing the search for suitable leukemia-specific antigens with a novel platform that combines pan-myeloid specific CART (such as CART-33) with an infusion of donor HSPC that are genetically engineered to lack CD33 and which are therefore resistant to killing by CART-33.

摘要/摘要（项目2） 免疫疗法彻底改变了对各种晚期恶性肿瘤的治疗。抗CD19嵌合 抗原受体重定向的T细胞（CART-11）在B细胞恶性肿瘤中特别成功。如何 将CART细胞疗法的成功转化为其他恶性肿瘤，例如急性髓样白血病（AML） 仍然是该领域的重要问题。 CART细胞疗法的关键要求是目标组织 可以消耗。 AML是造血茎/祖细胞（HSPC）的恶性肿瘤，共享细胞 具有正常HSPC和正常髓样后代的表面抗原，例如中性粒细胞和单核细胞。它 已经很清楚的是，缺乏AML特异性抗原是释放抗原的最大障碍 推车细胞对AML和其他髓样恶性肿瘤的力量。该项目的长期目标是 通过创建能够的AML特异性推车单元，为AML开发临床上可行的推车单元平台 在保留正常骨髓功能的同时，扩展并持续体内消除AML。中心假设 是抗CD33 CART细胞的耐用抗白血病作用可以与足够的水平共存 基因设计的CD33缺陷型造血。这将以三个具体目标来实现。目标 1，将制造高质量的抗CD33汽车T细胞。这些将是同种异体，供体衍生的 T细胞用比斯特朗式慢病毒载体转导的T细胞，该载体编码人性化的抗CD33-41BB-Zeta Car作为 以及CD20。在AIM 2中，将测试制造CD33缺乏人类HSPC的可行性和安全性 并将获得制造CD33缺陷HSPC的监管批准。在AIM 3中，临床试验将是 进行了一种结合CD33缺陷的，耐CAR的同种异体HCT的组合方法 AML患者的CART-33输注。这项研究将是重要的，因为它将有助于深度（ 临床反应）和广度（有资格进行潜在治疗疗法）针对治疗武器 AML。拟议研究的创新在于取代寻找合适的白血病特定的寻找 抗原具有新型平台，该平台将泛乳细胞特异性推车（例如CART-33）与输液相结合 供体HSPC的基因工程为缺乏CD33，因此具有抵抗力的杀戮 购物车-33。