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.
Patients with life-threatening cancers of the blood system such as leukemias, lymphomas, or myelodysplasia can be cured with a hematopoietic cell transplant from a healthy donor. However, patients may develop complications related to the graft or to the return of the disease (relapse) leading to poor outcomes after transplant. The strategies proposed in this application are focused on minimizing the risk of graft-related complications and of relapse and developing procedures that extend the possibility of transplantation to nearly all patients with candidate diseases.
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