A combination of anti-CD4 antibody treatment and DLI ameliorates GVHD while preserving GVT effects in murine allo-HSCT

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not only a well-established immunotherapy for hematologic malignancies, but is potentially useful for treating solid tumors refractory to available therapies. However, application of allo-HSCT to solid tumors is limited, despite the beneficial anti-tumor effects, by the risk of graft-versus-host disease (GVHD). CD4⁺ T cells have been implicated in several aspects of GVHD, and suppress anti-tumor CD8⁺ T cell responses. In the present study, we investigated clinically applicable allo-HSCT protocols designed to maximize anti-tumor effects while reducing the risk of GVHD. We used a mouse model of allo-HSCT with subcutaneous tumors. We found that myeloablative conditioning was associated with better inhibition of tumor growth but with severe acute GVHD. Early administration of anti-CD4 mAb substantially ameliorated GVHD, while preserving anti-tumor effects, leading to improved survival in myeloablative allo-HSCT. Late administration of anti-CD4 mAb also ameliorated GVHD to some extent. Donor lymphocyte infusion (DLI) in GVHD mice treated with anti-CD4 mAb further suppressed tumor growth without exacerbating GVHD. Collectively, our results suggest that myeloablative allo-HSCT followed by anti-CD4 mAb treatment and DLI may be a potent and safe immunotherapy for patients with cancers refractory to available therapies.

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