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: 9982244
• 负责人: CARL H. JUNE
• 金额: $ 24.16万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982244
• 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; engineered T cells; exome sequencing; experimental study; extracellular; 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多种晚期恶性肿瘤的治疗。抗CD19嵌合体 抗原受体重定向 T 细胞 (CART-19) 在 B 细胞恶性肿瘤中尤其成功。如何 将 CART 细胞疗法的成功应用于其他恶性肿瘤，例如急性髓系白血病 (AML) 仍然是该领域的一个重要问题。 CART细胞疗法的一个关键要求是靶组织 是消耗品。 AML 是造血干/祖细胞 (HSPC) 的恶性肿瘤，并共享细胞 具有正常 HSPC 和正常骨髓后代（例如中性粒细胞和单核细胞）的表面抗原。它 已经清楚的是，缺乏 AML 特异性抗原是释放 AML 的最大障碍。 CART 细胞对抗 AML 和其他骨髓恶性肿瘤的能力。该项目的长期目标是 通过创建能够 在体内扩展并持续存在以根除 AML，同时保留正常的骨髓功能。中心假设 抗 CD33 CART 细胞的持久抗白血病作用可以与足够水平的 基因工程CD33缺陷造血。这将通过三个具体目标来实现。瞄准 1、将生产高质量的可耗竭型抗CD33 CAR T细胞。这些将是同种异体的、来自供体的 用双顺反子慢病毒载体转导的 T 细胞，该载体编码人源化抗 CD33-41BB-zeta CAR 以及CD20。目标2将测试制造CD33缺陷型人类HSPC的可行性和安全性 并且将获得生产 CD33 缺陷型 HSPC 的监管批准。在目标 3 中，将进行临床试验 采用结合 CD33 缺陷、CAR 耐药的同种异体 HCT 的组合方法，然后 AML 患者的 CART-33 输注。这项研究意义重大，因为它将贡献深度（ 临床反应）和治疗手段的广度（潜在治愈的资格） 反洗钱。该研究的创新之处在于取代寻找合适的白血病特异性药物 具有将泛骨髓特异性 CART（例如 CART-33）与输注相结合的新型平台的抗原 供体 HSPC 经过基因工程改造，缺乏 CD33，因此能够抵抗杀伤 CART-33。