Determination of the efficacy of murine dendritic cell-based tumor vaccines in the setting of bone marrow transplantation.

Abstract

Murine tumor models have contributed much to our understanding of immune rejection processes and afford an opportunity for monitoring the in vivo therapeutic effects of cancer vaccines, adoptively transferred T cells, and bone marrow transplantation (BMT). Dendritic cells (DC), as potent antigen presenting cells, allow whole tumor lysates to be used as a source of tumor-associated antigen(s) for presentation to the immune system. This research project involves studies of murine DC-based cancer vaccines in the setting of syngeneic BMT. Tumor lysate-pulsed dendritic cells (TP-DC) could prime a specific and long-lasting antitumor immune response after BMT, which mediated the rejection of a lethal challenge of a weakly-immunogenic mammary carcinoma. In the therapeutic setting, repetitive immunizations of TP-DC could inhibit the growth of pre-existing tumor metastases as well. Because interleukin-7 (IL-7) has been shown by others to be capable of expediting hematolymphoid reconstitution and mediating antitumor immunity, this cytokine was combined with TP-DC immunizations in an attempt to enhance therapeutic efficacy. Although the systemic administration of IL-7 alone could stimulate hematolymphoid reconstitution, it had no effect on mediating antitumor immunity in the BMT setting. In addition, when used as an adjunct to TP-DC immunizations, IL-7 appeared to negate the antitumor immune response afforded by the vaccine. The antitumor therapeutic efficacy of TP-DC could, however, be further improved by an adoptive immunotherapy strategy. The bone marrow and lymph nodes of TP-DC immunized hosts contain tumor-reactive immune cells, which, when adoptively transferred to the BMT recipients, could mediate the regression of pre-existing metastatic tumors. The antitumor effect manifested by these tumor-reactive immune cells appeared to be tumor-specific and dependent on T cells. The secretion of Th1-type cytokines, including IFN-gamma and GM-CSF, by these tumor-reactive effector cells was detected. Collectively, these findings provide evidence for the antitumor efficacy of DC-based vaccines in the setting of syngeneic BMT and may have important implications for human clinical trials involving autologous bone marrow transplantations in cancer patients.