Cord Blood T Cell Therapy for Myeloid Malignancies

脐带血 T 细胞治疗骨髓恶性肿瘤

基本信息

批准号：
10478146
负责人：
JEFFREY J MOLLDREM
金额：
$ 35.61万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478146
关键词：
AML/MDS Acute Myelocytic Leukemia Adoptive Cell Transfers Adoptive Transfer Affinity Allogenic Animal Model Antibodies Antigens Binding Blood Bone Marrow CASP9 gene Cell Line Cell Therapy Cells Clinical Complex Correlative Study Cytolysis Cytotoxic T-Lymphocytes Data Development Disease Disease remission Dysmyelopoietic Syndromes Engineering Epitopes Goals HLA-A2 Antigen Hematologic Neoplasms Hematology Hematopoiesis Human IL3RA gene Immune Targeting Immune response Immunotherapy In Vitro Leukocyte Elastase Lymphoblastic Leukemia Malignant - descriptor Mediating Monoclonal Antibodies Morbidity - disease rate Mus Myelogenous Myeloid Cells Myeloid Leukemia Myeloproliferative disease Normal tissue morphology Outcome Parents Patient Care Patients Peptide Vaccines Peptide/MHC Complex Performance Status Phenotype Predisposition Proteinase 3 Proteins Refractory Relapse Research Resources Role Safety Sampling Source Stem cell transplant Surface T cell therapy T-Cell Receptor T-Lymphocyte Testing Tissues Toxic effect Transgenic Organisms Transplantation Treatment Protocols Tumor Lysis Syndrome Umbilical Cord Blood Umbilical Cord Blood Transplantation Work Xenograft Model acute myeloid leukemia cell antileukemic activity blood product cancer therapy cellular transduction chimeric antigen receptor chimeric antigen receptor T cells cytokine release syndrome engineered T cells experimental study graft vs host disease graft vs leukemia effect hematopoietic tissue high risk immune reconstitution in vivo leukemia leukemia initiating cell leukemia relapse leukemia treatment leukemic stem cell mortality mouse model novel patient derived xenograft model phase I trial pre-clinical preclinical study research clinical testing safety and feasibility safety testing standard care success suicide gene

项目摘要

PROJECT SUMMARY Acute myeloid leukemia (AML) is susceptible to immunotherapy as evidenced by the success of allogeneic (allo) stem cell transplantation (SCT) in this disease. Although allo-SCT can be curative in leukemia, it carries a high rate of treatment-related mortality and morbidity. This is primarily a result of off-target immune responses elicited by donor-derived cytotoxic T cells (CTL) within the SCT graft against normal tissues, a phenomenon known as graft-versus-host disease (GvHD), which occurs in up to 50% of patients following allo-SCT. Furthermore, AML relapse remains the leading cause of mortality following allo-SCT, highlighting the shortfalls of allo-SCT in providing long-lasting cures. In order to minimize GvHD, while taking advantage of the graft versus leukemia (GvL) effect, numerous leukemia-associated antigens (LAAs) have been identified and shown to elicit leukemia-specific immune responses. PR1 is an HLA-A2-restricted LAA that we identified in our lab and targeted using a monoclonal T cell receptor (TCR)-like antibody (8F4), a PR1-peptide vaccine, and PR1- CTL. In the current proposal, we plan to engineer chimeric antigen receptor (CAR) T cells that target PR1/HLA- A2 on the surface of AML using the 8F4 construct. The rationale for this proposal is that in view of the shortcomings and significant toxicities associated with allo-SCT, balanced by the susceptibility of AML to immunotherapy (i.e. allo-SCT), there is a critical need to develop novel immunotherapies to achieve disease elimination with minimal off-target toxicity. We plan to use 8F4 as the CAR since it has a very high affinity for the PR1/HLAA2 epitope presented by AML. We plan to use cord blood T cells as the cell source for engineering the 8F4-CAR T cells due to the success we have recently encountered in engineering and expanding sufficient numbers of effective 8F4-CAR T cells using cord blood products. Furthermore, we showed potency of the cord blood-derived 8F4-CAR-T cells in treating human AML in a mouse xenograft model. We will also introduce a caspase 9 (iCP9) suicide gene into the CAR construct, to increase the safety profile of the 8F4-CAR-T cells. Our central hypothesis is that immunotherapy with iCP9-8F4-CAR T cells engineered from cord blood T cells will eliminate PR1-expressing AML, with minimal off-target toxicity. We will (1) validate the safety and anti-leukemic activity of the iCP9-8F4-CAR-T cells in animal models using primary patient AML samples and cell lines; (2) test the safety and efficacy of the iCP9-8F4-CAR-T cells in patients with AML as a bridge to allo-SCT; and (3) study immune reconstitution and perform correlative studies using blood and bone marrow samples from iCP9-8F4-CAR-T cell recipients. After completion of our proposed studies, we anticipate that PR1-targeting adoptive cellular therapy using 8F4-CAR-T cells could become a standard therapy for patients with myeloid leukemia. In addition, our studies will elucidate the potential for cord blood T cells in the engineering of CAR-T cells for the treatment of cancer.

项目摘要急性髓样白血病（AML）容易受到免疫疗法的影响（Allo）该疾病中的干细胞移植（SCT）。尽管Allo-SCT可以在白血病中治愈，但它带有A 高度与治疗相关的死亡率和发病率。这主要是脱靶免疫反应的结果由供体衍生的细胞毒性T细胞（CTL）引起的SCT移植物针对正常组织的现象被称为移植物抗宿主病（GVHD），在Allo-SCT之后，多达50％的患者发生。此外，AML复发仍然是Allo-SCT之后死亡率的主要原因，突出了短缺提供长期治疗方法的Allo-SCT。为了最大程度地减少GVHD，利用移植与白血病（GVL）效应，已经确定并显示了许多与白血病相关的抗原（LAA）引起白血病特异性免疫反应。 PR1是我们在实验室中确定的HLA-A2限制性LAA 并使用单克隆T细胞受体（TCR）样抗体（8F4），PR1肽疫苗和PR1-靶向。 CTL。在当前的提案中，我们计划设计针对PR1/HLA-的嵌合抗原受体（CAR）T细胞使用8F4构建体在AML表面的A2。该提议的理由是，鉴于缺点和与Allo-SCT相关的显着毒性，并由AML的敏感性平衡免疫疗法（即Allo-SCT），需要开发新的免疫疗法以实现疾病的迫切需要消除最小的脱靶毒性。我们计划使用8F4作为汽车，因为它具有很高的亲和力 AML提出的PR1/HLAA2表位。我们计划使用脐带血细胞作为细胞来源由于我们最近在工程和使用脐带血产品扩大足够数量的有效8F4型T细胞。此外，我们表明在小鼠异种移植模型中治疗人AML中，脐带血的8F4-CAR-T细胞的效力。我们还将将caspase 9（ICP9）自杀基因引入汽车构建体，以提高 8F4-CAR-T细胞。我们的中心假设是对ICP9-8F4-CAR T细胞进行免疫疗法脐带血T细胞将消除表达PR1的AML，并具有最小的脱靶毒性。我们将（1）验证 ICP9-8F4-CAR-T细胞在动物模型中使用原发性患者AML的安全性和抗白血病活性样品和细胞系；（2）测试ICP9-8F4-CAR-T细胞在AML作为A的患者中的安全性和功效通往Allo-Sct的桥梁；（3）研究免疫结构并使用血液和骨骼进行相关研究来自ICP9-8F4-CAR-T细胞受体的骨髓样品。我们提出的研究完成后，我们预计使用8F4-CAR-T细胞使用Pr1靶向的产物细胞疗法可能会成为用于的标准疗法患有髓样白血病的患者。此外，我们的研究将阐明在 CAR-T细胞的工程治疗癌症。