Targeting FLT3 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

靶向 FLT3 治疗复发性或难治性急性髓系白血病

• 批准号: 10448509
• 负责人: Lihua Elizabeth Budde
• 金额: $ 47.94万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448509
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Affect; Allogenic; Antigen Targeting; Antigens; B lymphoid malignancy; B-Cell Lymphomas; Back; Biological; Blood; Bone Marrow; CAR T cell therapy; CD19 gene; Caring; Cell Line; Cell Therapy; Cell surface; Clinical; Clinical Research; Clinical Trials; Correlative Study; Data; Databases; Diagnosis; Disease; Dose; Effectiveness; Effector Cell; Engraftment; Enrollment; FDA approved; FLT3 gene; FLT3 inhibitor; Genetic Engineering; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterogeneity; Human; Human Engineering; Immune; Immune system; Immunotherapy; In Vitro; Infusion procedures; Institutional Review Boards; Interleukin-15; Lead; Leukemic Cell; Methodology; Morbidity - disease rate; Mus; Myelogenous; Natural Killer Cells; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Physicians; Procedures; Process; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Relapse; Reporting; Safety; Scientist; Surface; Surface Antigens; Survival Rate; T cell therapy; T-Lymphocyte; Therapeutic Intervention; TimeLine; Toxic effect; Tyrosine Kinase Inhibitor; Umbilical Cord Blood; Xenograft procedure; acute myeloid leukemia cell; antileukemic activity; chimeric antigen receptor; chimeric antigen receptor T cells; clinically relevant; cytotoxic; cytotoxicity; density; design; early phase clinical trial; effective therapy; engineered T cells; experience; experimental study; improved; improved outcome; in vivo; innovation; insight; leukemic stem cell; mortality; mouse model; mutational status; neoplastic cell; nonhuman primate; novel; older patient; overexpression; patient derived xenograft model; phase 1 study; pre-clinical; preclinical study; programs; receptor; receptor expression; sound; stem cell function; success; transduction efficiency; translational physician

PROJECT SUMMARY Chimeric antigen receptor (CAR)-engineered T cell therapy has revolutionized treatment for certain B cell malignancies, but similar successes for acute myeloid leukemia (AML) have not yet been shown, although interim results of early phase clinical trials, including our own, are promising. We have constructed a CAR that targets the type III receptor tyrosine kinase (RTK) called FLT3. Utilizing a patient-derived xenograft (PDX) model of FLT3(+) human AML, we have shown that infusion of human FLT3-CAR T cells prolonged survival of AML- bearing mice in the absence of other therapies. Further, FLT3-CAR T cells did not affect engraftment or survival of hematopoietic stem cells (HSCs) in mice bearing AML. The effectiveness of FLT3-CAR T cell therapy in AML will depend on (1) surface antigen density of FLT3 on AML blasts, including leukemic stem cells (LSC) relative to normal HSCs, and (2) the ability of other immune effector cells to contribute to the eradication of AML in vivo. To this end, we have discovered that treatment of AML blasts with an RTK inhibitor (TKI) upregulates the expression of FLT3 on the AML blast and the LSC in vivo, relative to FLT3 expression on normal HSCs. To advance a second cellular therapeutic intervention for AML, we have expressed the FLT3-CAR in human natural killer (NK) cells to generate FLT3-CAR NK cells, which demonstrated potent anti-leukemic activity against FLT3(+) AML. Collectively, these discoveries have led us to conclude that a program directed against FLT3(+) AML has strong rationale, is innovative and could result in a significant decline in mortality for a subset of AML patients. Therefore, the long-term objective of this proposal is to perform both preclinical and clinical studies that will best define an optimal strategy to reduce mortality from AML with FLT3-CAR cellular therapy, either alone or in combination with TKIs. Our central hypothesis is that targeting relapsed/refractory FLT3(+) AML with FLT3-CAR T cells or FLT3-CAR NK cells in combination with TKIs will improve outcomes in AML. In this proposal, we will assess the feasibility, safety and toxicity of performing a phase I study of human FLT3-CAR T cell therapy directed against FLT3(+) AML (Aim 1), we will determine the mechanism by which TKIs upregulate the surface density expression of FLT3 on LSCs and HSCs (Aim 2), and we will optimize a FLT3-CAR NK cell platform and assess its functionality against AML alone or combined with TKI (Aim 3). To accomplish these objectives, we have begun clinical manufacturing of FLT3-CAR T cells to treat eligible patients with refractory or relapsed AML; we will utilize both human AML cell lines and patients' AML blasts in vitro as well as in vivo along with our PDX model for our correlative and preclinical studies evaluating FLT3-CAR T and FLT3-CAR NK cells in combination with TKI. Upon conclusion, we will understand how best to optimize cellular immune therapy to cure AML. Further insight into this process, as will result from the implementation and completion of this proposal is impactful as it will ultimately lead to a reduction in mortality for select patients suffering from AML.

项目摘要 嵌合抗原受体（CAR）工程化T细胞疗法已经彻底改变了某些B细胞的治疗 恶性肿瘤，但类似的成功急性髓细胞白血病（AML）尚未显示，虽然中期 早期临床试验的结果，包括我们自己的试验，是有希望的。我们制造了一辆车， III型受体酪氨酸激酶（RTK），称为FLT 3。利用患者来源的异种移植物（PDX）模型， FLT 3（+）人AML，我们已经证明输注人FLT 3-CAR T细胞延长了AML-1的存活。 在没有其他治疗的情况下进行。此外，FLT 3-CAR T细胞不影响植入或存活。 造血干细胞（HSC）在小鼠携带AML。FLT 3-CAR T细胞治疗AML的有效性 将取决于（1）AML原始细胞上FLT 3的表面抗原密度，包括白血病干细胞（LSC）相对 正常HSC，和（2）其他免疫效应细胞有助于体内AML根除的能力。 为此，我们已经发现用RTK抑制剂（TKI）处理AML母细胞上调了细胞凋亡。 FLT 3在体内AML原始细胞和LSC上的表达，相对于FLT 3在正常HSC上的表达。到 为了推进AML的第二种细胞治疗干预，我们已经在人类自然细胞中表达了FLT 3-CAR， FLT 3-CAR NK细胞，其表现出针对白血病的有效抗白血病活性。 FLT3（+）AML。总的来说，这些发现使我们得出结论，针对FLT 3（+）的程序 AML有很强的理论基础，具有创新性，可导致AML亚组的死亡率显著下降 患者因此，本提案的长期目标是进行临床前和临床研究 这将最好地定义使用FLT 3-CAR细胞疗法降低AML死亡率的最佳策略， 单独使用或与TKI联合使用。我们的中心假设是，靶向复发性/难治性FLT 3（+）AML FLT 3-CAR T细胞或FLT 3-CAR NK细胞与TKI的联合治疗将改善AML的结局。在这 根据该提案，我们将评估进行人类FLT 3-CAR T I期研究的可行性、安全性和毒性 针对FLT 3（+）AML的细胞疗法（目的1），我们将确定TKI上调的机制， FLT 3在LSC和HSC上的表面密度表达（目标2），我们将优化FLT 3-CAR NK细胞 平台，并评估其单独或与TKI联合治疗AML的功能（目的3）。完成这些 我们已经开始临床生产FLT 3-CAR T细胞，用于治疗符合条件的难治性或 我们将在体外和体内沿着利用人AML细胞系和患者的AML原始细胞， 我们的PDX模型用于评估FLT 3-CAR T和FLT 3-CAR NK细胞的相关和临床前研究 与TKI结合。结论是，我们将了解如何最好地优化细胞免疫治疗， 治愈AML。通过执行和完成本提案，进一步了解这一进程 是有影响力的，因为它最终将导致患有AML的选定患者的死亡率降低。