Clinical studies of cell-based immunotherapies have included both patient-specific (autologous) and non-patient-specific (allogeneic) approaches. Major concerns in using allogeneic immunotherapies are that the induced immune responses may be predominantly directed against the allogeneic HLA molecules of the cellular immunotherapy and not against its potential tumor antigens and that only the allogeneic responses will be enhanced when the immunotherapies are combined with immune checkpoint regulators in an effort to enhance overall immunotherapy potency. To evaluate these possibilities, studies were performed using the GM-CSF-secreting B16F1 cell line as autologous immunotherapy (Auto) and the same cell line modified to over-express the MHC molecule K(d) to generate an immunotherapy that expresses an allogeneic component (Allo) when injected into C57/Bl6 mice. The goal was to compare the specific anti-tumor immune responses induced by these two immunotherapies, which share an identical antigen repertoire, with the exception of the allogeneic MHC class I molecule expressed by the Allo cells, and have identical GM-CSF-secretion levels. Both immunotherapies provided similar therapeutic benefit to tumor-bearing animals with a trend towards a more pronounced tumor growth delay in animals injected with the Allo immunotherapy. This correlated with a significant increase in the number of activated DCs and T-cells in the DLN of Allo-treated animals. In addition, persistent infiltration of effector CD8(+) T-cells was detected in the tumors of animals treated with the Allo immunotherapy, which correlated with a trend towards a greater antigen-specific T-cell response in these animals. When combined with the immune checkpoint regulator anti-PD-1, tumor-specific and allogeneic immune responses were equally enhanced. Thus, the ability of an allogeneic tumor cell immunotherapy to induce a therapeutic anti-tumor immune response is comparable, if not superior, to an autologous tumor cell immunotherapy and its anti-tumor potency can be enhanced when combined with immunomodulatory compounds.