Project 4: Off-the-shelf engineered cord blood-derived natural killer cells for the treatment acute lymphoblastic leukemia

项目 4：现成的工程化脐带血自然杀伤细胞，用于治疗急性淋巴细胞白血病

• 批准号: 10247506
• 负责人: Katy Rezvani
• 金额: $ 27.24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-05 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247506
• 关键词: Acute Lymphocytic Leukemia; Address; Adoptive Cell Transfers; Adoptive Transfer; Adult; Advanced Malignant Neoplasm; Advisory Committees; Allogenic; Antigen Targeting; Antigens; Autologous; B lymphoid malignancy; B-Lymphocytes; Blood Banks; CAR T cell therapy; CASP9 gene; CD19 gene; Cancer Center; Cancer Patient; Cell Therapy; Cell physiology; Cells; Clinic; Clinical; Clinical Data; Clinical Protocols; Clinical Research; Clinical Trials; Correlative Study; Data; Disadvantaged; Disease; Doctor of Medicine; Dominant Genes; Dominant-Negative Mutation; Dose; Effector Cell; Engineering; Equipment and supply inventories; Exhibits; Freezing; Generations; Genetic Engineering; Human; In Vitro; Individual; Innate Immune System; Institutional Review Boards; Interleukin-15; Laboratories; Leukapheresis; Logistics; Lymphoid; Malignant Neoplasms; Measures; Mediating; Methods; Modality; Mus; Natural Killer Cell toxicity; Natural Killer Cells; Patient-Focused Outcomes; Patients; Pharmacology; Positioning Attribute; Proliferating; Protocols documentation; Recombinant DNA; Refractory; Regulation; Relapse; Reporting; Reproducibility; Research; Retroviral Vector; Risk; Safety; Sampling; Series; Signal Transduction; Source; Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Texas; Therapeutic; Toxic effect; Transforming Growth Factor beta; Umbilical Cord Blood; Universities; acute lymphoblastic leukemia cell; advanced disease; alpha-beta T-Cell Receptor; antileukemic activity; base; cancer cell; cancer therapy; cellular transduction; chimeric antigen receptor; chimeric antigen receptor T cells; chimeric gene; clinically relevant; conventional therapy; cost effective; cytokine; cytokine release syndrome; cytotoxicity; engineered NK cell; graft vs host disease; immunoengineering; immunotherapy clinical trials; improved outcome; in vivo; individual patient; innovation; leukemia; next generation; novel; novel strategies; pre-clinical; preclinical study; receptor; reconstitution; refractory cancer; relapse risk; response; safety testing; screening; suicide gene; tumor; tumor-immune system interactions; vector

Summary: The past several years have seen tremendous advances in the engineering of immune effector cells as therapy for cancer. However, chimeric antigen receptor (CAR)-modified T-cells have a number of limitations. The generation of an autologous product for each individual patient is logistically cumbersome and restrictive for widespread clinical use. The manufacturing of CAR T-cells often takes several weeks, making it impractical for patients with rapidly advancing disease. Furthermore, it is not always possible to generate clinically relevant doses of CAR T-cells from heavily pre-treated, often lymphopenic patients. A previously collected allogeneic product could overcome these limitations; however, allogeneic T-cells (even if HLA-matched) carry a significant risk of graft-versus-host disease (GVHD) mediated through their native αβ T-cell receptor prohibiting their use as a clinical product without further manipulation to eliminate the T cell receptor. Natural killer (NK) cells provide an extremely attractive alternative to T-cells for CAR engineering. NK cells do not cause GVHD and thus open opportunities to produce an off-the-shelf product for immediate clinical use. Moreover, as engineered NK cells should also retain their full array of native receptors, they have the potential to exert cytotoxicity through mechanisms other than that dictated by the specificity of the CAR, which in principle could reduce the risk of relapse mediated by loss of CAR-targeted antigen, as reported for CAR-T cell therapy. Autologous NK cells can be reproducibly generated in vitro, but have extremely limited activity against autologous tumor which cannot be overcome by CAR engineering. Cord blood (CB) is a readily available source of allogeneic NK cells with clear advantages. CB is available as an off-the-shelf frozen product, an advantage that has been bolstered by methods to generate large numbers of highly functional NK cells from frozen CB units ex vivo. The generation of CAR-transduced NK cells from frozen CB units stored in large global CB bank inventories holds promise for widespread scalability that cannot be replicated with individual adult donors who require screening and leukapheresis. In Aim 1 we will perform the first-inhuman clinical trial to test the safety and efficacy of CB-NK cells engineered to express a CAR against CD19 (a B cell-specific antigen), to ectopically produce IL-15 to support their in vivo proliferation and persistence, and to express a suicide gene, based on IC9, that will address safety concerns related to the potential risk of direct toxicity; In Aim 2 we will apply highly innovative correlative studies to describe the therapeutic potential of the clinical trial; Aim 3 in preclinical murine studies, we will protect the transduced NK cells from the TGF-β/SMAD signaling axis using a novel retroviral construct that, in addition to CAR.CD19 and IL-15, includes the gene for the dominant-negative version of human TGFβ receptor II (TGFβ- DNRII) for next-generation clinical studies.

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