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T细胞疗法已彻底改变了某些B细胞的治疗 恶性肿瘤，但急性髓样白血病（AML）的成功尚未显示，尽管临时 早期临床试验（包括我们自己的）的结果是有希望的。我们已经建造了一个针对的汽车 III型受体酪氨酸激酶（RTK）称为FLT3。利用患者衍生的异种移植（PDX）模型 flt3（+）人类AML，我们已经表明，人类Flt3-car T细胞的输注延长了AML- 在没有其他疗法的情况下轴承小鼠。此外，FLT3-CAR T细胞不影响植入或存活 带有AML的小鼠中造血干细胞（HSC）的FLT3-CAR T细胞疗法在AML中的有效性 将取决于AML Blast上FLT3的（1）表面抗原密度，包括白血病干细胞（LSC）相对 达到正常的HSC，以及（2）其他免疫效应细胞有助于消除AML体内的能力。 为此，我们发现用RTK抑制剂（TKI）对AML爆炸的处理可上调 相对于正常HSC上的FLT3表达，在AML BLAST和LSC IN VIVO上的FLT3表达。到 推进第二次细胞治疗干预措施，我们在人类天然中表达了FLT3卡车 杀手（NK）细胞生成FLT3-CAR NK细胞，该细胞表现出有效的抗白血病活性 FLT3（+）AML。总的来说，这些发现使我们得出结论，一项针对FLT3（+）的计划 AML具有很强的理由，具有创新性，并且可能导致AML子集的死亡率大幅下降 患者。因此，该提案的长期目标是同时进行临床前和临床研究 这将最好定义一种最佳策略，即通过FLT3-CAR细胞疗法从AML降低死亡率，既可以 单独或与TKI结合。我们的中心假设是靶向复发/难治性FLT3（+）AML 与FLT3-CAR T细胞或FLT3-CAR NK细胞与TKI结合使用将改善AML的预后。在这个 提案，我们将评估对人类FLT3-CAR T进行I期研究的可行性，安全性和毒性 针对FLT3（+）AML的细胞疗法（AIM 1），我们将确定TKI上调的机制 LSC和HSC上FLT3的表面密度表达（AIM 2），我们将优化FLT3-CAR NK细胞 平台并评估单独使用AML或与TKI结合的功能（AIM 3）。完成这些 目的，我们已经开始对FLT3-CAR T细胞的临床制造，以治疗难治性或 复发AML；我们将在体外以及沿着体内利用人类AML细胞系和患者的AML爆炸 使用我们的PDX模型，用于评估FLT3-CAR T和FLT3-CAR NK细胞的相关和临床前研究 结合TKI。总结一下，我们将了解如何最好地优化细胞免疫治疗 治愈AML。由于本提案的实施和完成将进一步了解此过程 具有影响力，因为它最终会导致患有AML的精选患者死亡率降低。