Abstract Donor immune-mediated anti-neoplastic effects make the greatest contribution to the durable disease remissions obtained in hematological malignancies following allogeneic hematopoietic cell transplantation (a-HCT). Recent studies have demonstrated that clinically meaningful graft-versus-tumor (GVT) effects can also be induced against select solid tumors following a-HCT. GVT effects have been most extensively documented in RCC, where response rates in the range of 20%–50% have been reported. Unfortunately, death from eventual disease progression and morbidity from graft-versus-host disease (GVHD) limit a broader application of a-HCT to manage this tumor. In order to explore mechanisms underlying GVT effects against RCC, and to optimize outcome following transplantation, we sought to establish a murine MHC-compatible, but mHA-disparate a-HCT model in mice with metastatic RCC. Recipient Balb/C (H-2d) mice were conditioned with a myeloablative regimen consisting of 950cGy total body irradiation and transplanted with bone marrow cells and splenocytes from either syngeneic (Balb/C) or allogeneic, mHA mismatched B10.d2 (H-2d) mice. Murine RCC cells (RENCA, 1x105 cells/mouse) were injected into the tail veins of both Balb/C recipient groups 3 days after transplantation and were followed for survival and the establishment of metastatic pulmonary lesions. Recipients of allo-HCT had improved survival (mean 54±2 days) compared to those receiving syngeneic transplants (mean 31±0 days: p<0.001). At death, 4/4 mice receiving syngeneic transplants demonstrated widespread pulmonary metastatic disease while none of the allo-HCT recipients (n=4) developed metastatic disease (Figure 1A). A slight improvement in survival for allo-HCT recipients was also noted when Balb/C mice were injected subcutaneously with RENCA (1x105 cells) three days following transplantation (31±0 for syngeneic and 40±7 for allogeneic recipients; p=0.04). Serial measurements of subcutaneous tumor nodules (Figure 1B) revealed significantly slower tumor growth in allo-HCT recipients (mean volume = 272mm3, day 31) compared to recipients of syngeneic grafts (mean volume = 11mm3, day 31). Graft-versus-host disease (GVHD) characterized by alopecia, weight loss and diarrhea occurred at a median 28±3 days after transplantation and was the primary cause of death in a-HCT recipients. Unlike previously reported murine a-HCT models for solid tumors, pre-transplant priming of donor mice with recipient splenocytes or tumor cells was not required for the generation of GVT effects. These data suggest donor immune responses against minor histocompatibility antigens can mediate potent GVT effects against RCC following allo-HCT. This murine model will serve as a platform for the development of tumor- targeted a-HCT strategies aimed at refining and enhancing GVT effects while mitigating GVHD. Figure Figure