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scFvPD1-FLT3 CAR T Cells for the Treatment of Relapsed Acute Myeloid Leukemia

scFvPD1-FLT3 CAR T 细胞用于治疗复发性急性髓系白血病

基本信息

批准号：
9765792
负责人：
Jianhua Yu
金额：
$ 22.58万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765792
关键词：
Acute Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Affect Allogenic Animal Model Antibodies Antibody Therapy Antigen Targeting Antigens Bystander Effect CAR T cell therapy CD34 gene CD94 Antigen Cancer Patient Cell Line Cells Cessation of life Chronic Lymphocytic Leukemia Clinic Clinical Treatment Combined Modality Therapy Data Dendritic Cells Development Disease Disease-Free Survival Drug resistance Engineering FLT3 gene Glioblastoma Grant Hematologic Neoplasms Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human IL3RA gene ITAM Immune Immune checkpoint inhibitor Immune response Immunodeficient Mouse In Vitro Infection Ligands Light Malignant Neoplasms Metastatic malignant neoplasm to brain Monoclonal Antibodies Morbidity - disease rate Mus Mutation Myeloid Cells Natural Killer Cells Normal Cell Normal tissue morphology Outcome Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Preclinical Testing Published Comment Publishing Receptor Activation Receptor Cell Receptor Protein-Tyrosine Kinases Recovery Recurrent disease Refractory Relapse Reporting Resistance Rest SLEB2 gene Signal Transduction Solid Neoplasm Stem cells Surface T-Cell Activation T-Lymphocyte Testing Toxic effect Transplantation Treatment Efficacy Treatment Protocols Tumor Antigens Work Xenograft procedure acute myeloid leukemia cell anti-PD-1 autocrine base cancer immunotherapy chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical efficacy design effective therapy engineered T cells exhaust exhaustion experience fighting functional restoration graft vs host disease high reward high risk immune checkpoint blockade improved in vitro testing in vivo innovation interest leukemia malignant breast neoplasm meetings mortality mouse model neoplastic cell novel novel therapeutics older patient outcome forecast paracrine pre-clinical receptor self-renewal standard care targeted treatment tumor tumor microenvironment vector

项目摘要

Project Summary Acute Myeloid leukemia (AML) has a median survival of only six months in relapsed elderly patients. For this reason, there is great interest in developing targeted therapeutics to improve efficacy while decreasing morbidity. Recent reports of chimeric antigen receptor (CAR) T cells targeting antigens expressed on acute and chronic lymphocytic leukemia shed light on novel immune-based approaches for relapsed and/or refractory hematological malignancies. However, CAR T cells have not yet been successful in treating AML in the clinic due to the lack of an ideal target, as some reported targets (e.g., CD123 and CD33) deplete hematopoietic stem cells and/or myeloid cells. In contrast, our preliminary data showed that targeting FLT3 with CAR T cells is relatively safer because FLT3-CAR T cells do not kill healthy peripheral blood mononuclear cells in vitro and do not significantly affect self-renewal and repopulation of hematopoietic stem cells. Thus, we believe FLT3 is a relatively better target for CAR T cells in the treatment of AML. We therefore generated CAR T cells targeting FLT3. FLT3-CAR T cells enhance in vitro eradication of AML blasts isolated from patients and eliminate human AML cells engrafted into immunodeficient mice. T cells (including CAR T cells) can become exhausted and suppress immune responses when fighting tumor cells in the tumor microenvironment. This is at least partially due to the increased expression of the PD-1 receptor, a key checkpoint inhibitor modulating T cell activation. The anti-PD-1 T cell checkpoint blockade antibody is designed to reverse T cell exhaustion and has shown promising clinical efficacy for the treatment of various cancers. Our group and others have previously demonstrated that PD-1 is also expressed on NK cells in cancer patients but not in resting NK cells. Thus, it is more effective to combine CAR T cells and PD-1 checkpoint blockade to enhance the power of both NK cells and T cells. In this study, we added a frame to the FLT3 CAR construct that we have generated to express anti-PD-1 single chain antibodies (scFvPD1). We have engineered T cells with this construct to generate so-called scFvPD1-FLT3 CAR T cells that are able to target FLT3 in AML using FLT3-CAR T cells simultaneously expressing soluble scFvPD1 to restore the function of exhausted T cells. CAR T cells and patient NK cells also express inhibitory PD-1. Thus, the soluble scFvPD1 produced by scFvPD1-FLT3 CAR T cells will further augment the antitumor activity of FLT3-CAR T cells in an autocrine manner, and endogenous NK and T cells in a paracrine manner. With this multipronged attack to augment immune responses against tumor cells, we believe our approach has the potential to successfully treat relapsed and/or refractory AML. We have three Aims proposed to test scFvPD1-FLT3 CAR T cells in vitro and in vivo: Aim 1, further in vitro testing of scFvPD1-FLT3 CAR T cells; Aim 2, In vivo preclinical testing of scFvPD1- FLT3 CAR T cell efficacy; Aim 3, Combination therapy using scFvPD1-FLT3 CAR T cells and midostaurin, a drug recently approved by the U.S. FDA, which we have found induces FLT3 surface expression on AML blasts.

项目摘要急性髓系白血病（AML）复发的老年患者中位生存期仅为6个月。为此因此，人们对开发靶向疗法以提高疗效同时降低发病率非常感兴趣。嵌合抗原受体（CAR）T细胞靶向急性和慢性炎症表达的抗原的最新报道淋巴细胞性白血病揭示了治疗复发性和/或难治性血液病的新的免疫方法恶性肿瘤。然而，由于缺乏CAR T细胞，CAR T细胞在临床上尚未成功治疗AML。理想的目标，如一些报道的目标（例如，CD 123和CD 33）耗尽造血干细胞和/或骨髓细胞相比之下，我们的初步数据显示，用CAR T细胞靶向FLT 3相对更安全。因为FLT 3-CAR T细胞在体外不杀死健康的外周血单核细胞，影响造血干细胞的自我更新和再增殖。因此，我们认为FLT 3是一个相对较好的靶点 CAR T细胞在AML治疗中的应用因此，我们产生了靶向FLT 3的CAR T细胞。FLT 3-CAR T细胞增强从患者中分离的AML原始细胞的体外根除，并消除移植到免疫缺陷小鼠T细胞（包括CAR T细胞）可能会耗尽并抑制免疫反应在肿瘤微环境中对抗肿瘤细胞。这至少部分是由于增加的表达 PD-1受体是调节T细胞活化的关键检查点抑制剂。抗PD-1 T细胞检查点阻断抗体旨在逆转T细胞耗竭，并已显示出有希望的临床疗效，治疗各种癌症。我们的研究小组和其他人以前已经证明，PD-1也表达在对癌症患者的NK细胞有影响，但对静息NK细胞没有影响。因此，将联合收割机CAR T细胞和 PD-1检查点阻断以增强NK细胞和T细胞的能力。在这项研究中，我们增加了一个框架，我们已经产生的表达抗PD-1单链抗体（scFvPD 1）的FLT 3 CAR构建体。我们已经用这种构建体改造了T细胞，以产生所谓的scFvPD 1-FLT 3 CAR T细胞，使用同时表达可溶性scFvPD 1的FLT 3-CAR T细胞靶向AML中的FLT 3以恢复功能耗尽的T细胞。CAR T细胞和患者NK细胞也表达抑制性PD-1。因此，可溶性scFvPD 1 scFvPD 1-FLT 3 CAR T细胞产生的抗体将进一步增强FLT 3-CAR T细胞的抗肿瘤活性，自分泌方式，和内源性NK和T细胞的旁分泌方式。通过这种多管齐下的攻击，增强对肿瘤细胞的免疫反应，我们相信我们的方法有可能成功地治疗复发性和/或难治性AML。我们提出了三个目的来在体外和体内测试scFvPD 1-FLT 3 CAR T细胞。体内：目标1，scFvPD 1-FLT 3 CAR T细胞的进一步体外测试;目标2，scFvPD 1-FLT 3 CAR T细胞的体内临床前测试。 FLT 3 CAR T细胞功效;目的3，使用scFvPD 1-FLT 3 CAR T细胞和药物米多鲁肽的联合治疗最近由美国FDA批准，我们发现其诱导AML母细胞上的FLT 3表面表达。