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: 10318050
• 负责人: Lihua Elizabeth Budde
• 金额: $ 48.92万
• 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/10318050
• 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.

项目概要 嵌合抗原受体 (CAR) 工程 T 细胞疗法彻底改变了某些 B 细胞的治疗方法 恶性肿瘤，但尚未在急性髓系白血病 (AML) 方面取得类似的成功，尽管目前已取得了阶段性成果 包括我们自己在内的早期临床试验的结果是有希望的。我们构建了一个 CAR 目标 III 型受体酪氨酸激酶 (RTK)，称为 FLT3。利用患者来源的异种移植（PDX）模型 FLT3(+) 人类 AML，我们已经证明，输注人 FLT3-CAR T 细胞可延长 AML- 的存活率 在没有其他治疗的情况下生育小鼠。此外，FLT3-CAR T 细胞不影响植入或存活 患有 AML 的小鼠体内造血干细胞 (HSC) 的变化。 FLT3-CAR T细胞治疗AML的有效性 将取决于 (1) AML 母细胞上的 FLT3 表面抗原密度，包括白血病干细胞 (LSC) 相对值 (2) 其他免疫效应细胞有助于体内根除 AML 的能力。 为此，我们发现用 RTK 抑制剂 (TKI) 治疗 AML 母细胞可上调 相对于正常 HSC 上的 FLT3 表达，体内 AML 母细胞和 LSC 上的 FLT3 表达。到 推进针对 AML 的第二种细胞治疗干预，我们已在人类天然细胞中表达了 FLT3-CAR 杀伤 (NK) 细胞产生 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，针对 FLT3(+) 的程序 AML 有充分的理由、具有创新性，可能会导致 AML 子集的死亡率显着下降 患者。因此，该提案的长期目标是进行临床前和临床研究 这将最好地确定通过 FLT3-CAR 细胞疗法降低 AML 死亡率的最佳策略 单独或与 TKI 联合使用。我们的中心假设是针对复发/难治性 FLT3(+) AML FLT3-CAR T 细胞或 FLT3-CAR NK 细胞与 TKI 联合使用将改善 AML 的治疗效果。在这个 根据提案，我们将评估进行人类FLT3-CAR T I期研究的可行性、安全性和毒性 针对 FLT3(+) AML 的细胞疗法（目标 1），我们将确定 TKI 上调的机制 FLT3在LSC和HSC上的表面密度表达（目标2），我们将优化FLT3-CAR NK细胞 平台并评估其单独针对 AML 或与 TKI 结合的功能（目标 3）。为了完成这些 为了实现这一目标，我们已经开始 FLT3-CAR T 细胞的临床生产，以治疗符合条件的难治性或难治性患者。 复发性 AML；我们将在体外和体内利用人类 AML 细胞系和患者的 AML 母细胞 使用我们的 PDX 模型进行相关和临床前研究，评估 FLT3-CAR T 和 FLT3-CAR NK 细胞 与 TKI 联合使用。最后，我们将了解如何最好地优化细胞免疫疗法 治愈 AML。对该流程的进一步深入了解，将因该提案的实施和完成而产生 具有影响力，因为它最终将降低特定 AML 患者的死亡率。