Cord Blood T Cell Therapy for Myeloid Malignancies

脐带血 T 细胞治疗骨髓恶性肿瘤

• 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
• 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

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 急性髓性白血病（AML）对免疫疗法敏感，如通过同种异体移植的成功所证明的。 （异基因）干细胞移植（SCT）在这种疾病。虽然allo-SCT可以治愈白血病，但它携带了一种 与治疗相关死亡率和发病率高。这主要是脱靶免疫反应的结果 由SCT移植物内的供体来源的细胞毒性T细胞（CTL）引起的对正常组织的杀伤， 称为移植物抗宿主病（GvHD），发生在allo-SCT后高达50%的患者中。 此外，AML复发仍然是allo-SCT后死亡的主要原因，突出了其不足之处。 allo-SCT在提供长期治疗方面的优势。为了尽量减少GvHD，同时利用移植物 与白血病（GvL）的影响，许多白血病相关抗原（LAAs）已被确定和显示 引发白血病特异性免疫反应PR 1是我们在实验室中鉴定的HLA-A2限制性LAA 并使用单克隆T细胞受体（TCR）样抗体（8 F4）、PR 1-肽疫苗和PR 1-肽疫苗靶向， CTL.在目前的提案中，我们计划设计靶向PR 1/HLA-1的嵌合抗原受体（CAR）T细胞。 使用8 F4构建体在AML表面上的A2。这项建议的理由是，鉴于 与allo-SCT相关的缺点和显著毒性，由AML对 在免疫疗法（即allo-SCT）中，迫切需要开发新的免疫疗法以实现疾病的治疗。 以最小的脱靶毒性消除。我们计划使用8 F4作为CAR，因为它具有非常高的亲和力， AML的PR 1/HLAA 2表位。我们计划使用脐带血T细胞作为细胞来源， 由于我们最近在工程设计中遇到的成功， 使用脐带血产品扩增足够数量的有效8 F4-CAR T细胞。此外，我们还展示了 在小鼠异种移植模型中，脐带血来源的8 F4-CAR-T细胞在治疗人AML中的效力。我们 还将在CAR构建体中引入胱天蛋白酶9（iCP 9）自杀基因，以增加CAR的安全性。 8 F4-CAR-T细胞。我们的中心假设是，使用从人源化的iCP 9 - 8 F4-CAR T细胞进行的免疫治疗可以有效地抑制肿瘤细胞的增殖。 脐带血T细胞将以最小的脱靶毒性消除表达PR 1的AML。我们将（1）验证 iCP 9 - 8 F4-CAR-T细胞在使用原发性患者AML的动物模型中的安全性和抗白血病活性 样本和细胞系;（2）测试iCP 9 - 8 F4-CAR-T细胞在AML患者中作为 移植到allo-SCT的桥梁;（3）研究免疫重建，并利用血液和骨进行相关研究 来自iCP 9 - 8 F4-CAR-T细胞接受者的骨髓样品。在完成我们建议的研究后，我们预计 使用8 F4-CAR-T细胞的PR 1靶向过继性细胞疗法可能成为一种标准疗法， 髓系白血病患者。此外，我们的研究将阐明脐带血T细胞的潜力， 工程化CAR-T细胞用于治疗癌症。