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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：
10247038
负责人：
JEFFREY J MOLLDREM
金额：
$ 35.58万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247038
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.

项目总结