Program Integration and management

程序集成和管理

• 批准号: 8933144
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 1.91万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-02 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8933144
• 关键词: Accounting; Acute Graft Versus Host Disease; Acute leukemia; Address; Adoptive Immunotherapy; Allogenic; Allografting; Astatine; B lymphoid malignancy; Canis familiaris; Cell Therapy; Cell Transplants; Chimerism; Clinical; Comorbidity; Coupled; Cyclophosphamide; Cyclosporine; Data Analyses; Deposition; Development; Disease; Dose; Dysmyelopoietic Syndromes; Elderly; Failure; Funding; Gene-Modified; Goals; Graft-Versus-Tumor Induction; Grant; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Hour; Immunosuppression; Incidence; Infection; Infusion procedures; Label; Life; Link; Lymphoma; Malignant Neoplasms; Malignant lymphoid neoplasm; Maximum Tolerated Dose; Methotrexate; Modeling; Monoclonal Antibodies; Natural Killer Cells; Outcome; PTPRC gene; Patients; Pharmaceutical Preparations; Procedures; Protocols documentation; Radial; Radioisotopes; Recurrent disease; Regimen; Regulatory T-Lymphocyte; Relapse; Risk; Stem cells; System; T-Cell Activation; T-Lymphocyte; Therapeutic immunosuppression; Translating; Transplant Recipients; Transplantation; Treatment Failure; Tumor Burden; Whole-Body Irradiation; base; caspase-9; chronic graft versus host disease; clinically relevant; conditioning; disorder prevention; fludarabine; graft vs host disease; hematopoietic cell transplantation; immune function; leukemia/lymphoma; mortality; novel strategies; pre-clinical; preclinical study; prevent; programs; public health relevance; success; suicide gene; tool; treatment strategy; tumor eradication

ABSTRACT - OVERALL More than 1,850 elderly or medically infirm patients with advanced hematologic malignancies have received HLA-matched related or unrelated or HLA-haploidentical hematopoietic cell transplantation (HCT) on reduced- intensity conditioning regimens that were translated from canine studies under this grant. While overall 5-year survivals were encouraging, we identified two problems that accounted for nearly all of the treatment failures: non-relapse mortality (NRM) from graft-versus-host-disease (GVHD)-related causes and relapse-related mortality. Moreover, acute GVHD did not convey GVT effects. In contrast, chronic GVHD showed significant GVT effects; however, this benefit was offset by increased NRM. These findings set the theme for the current grant. We propose three projects, one preclinical and two clinical, which focus on reducing GVHD-related NRM and relapse mortality. The theme of the preclinical Project 1 is to minimize GVHD-related NRM. We will use a DLA-mismatched canine model that has served to develop nearly all of our GVHD prevention and treatment used clinically. Aim 1 will focus on preventing acute GVHD, and Aim 2 proposes new treatment strategies for chronic GVHD. Developing GVHD is consistent with T-cell activation despite standard immunosuppression. We have generated or identified monoclonal antibodies (mAbs) specific for canine T-cell regulatory molecules. Guided by the results of linked mechanistic studies, we will use the mAbs to block T-cell costimulation and/or downregulate or eliminate activated T-cells. We hypothesize that the current high incidence of acute GVHD can be reduced and that chronic GVHD can be treated more effectively, reducing both the duration of the current long-term immunosuppressive therapy (median 2.5 years) for transplanted patients and the risk of fatal infections. The clinical Projects 2 and 3 address relapse in patients with advanced acute leukemias and myelodysplasias (Project 2) and B-cell malignancies (Project 3) as well as extending allogeneic HCT to include patients who lack HLA-matched donors. Both projects propose dose-escalation studies for HLA-matched HCT recipients using an anti-CD45 mAb coupled to an alpha-emitting radionuclide, astatine-211 (211At), in addition to the standard fludarabine (FLU)/2Gy total body irradiation (TBI) conditioning regimen. This novel approach is based on extensive preclinical studies in our canine model. We anticipate a significant reduction in pretransplant tumor burden from the addition of the 211At-labeled mAb and, thus, a corresponding reduction in relapse risk after HCT. Both projects will also address the relapse problem in HLA-haploidentical recipients. Project 2 proposes dose-escalation studies with 211At-labeled anti-CD45 mAb in addition to FLU/cyclophosphamide/2Gy TBI conditioning. Project 3 proposes a study of natural killer cell infusions from the HLA-haploidentical donors after reduced-intensity conditioning. A concurrent trial after myeloablative conditioning will study augmentation of HLA-haploidentical HCT with gene-modified T-cells.

摘要-总体