Potentiation of immunologic responsiveness to dendritic cell-based tumor vaccines by recombinant interleukin-2

PURPOSE Dendritic cells (DC) can elicit potent immune responses to tumors through t heir capacity to efficiently process and present tumor-associated antigens. In a variety of animal tumor models, vaccines based on tumor lysate-pulsed DC (TP-DC) have been shown to effectively immunize against lethal tumor ch allenges as well as to treat established growing tumors at skin and organ s ites. The antitumor effects elicited by TP-DC-based vaccines in vivo have b een shown to be mediated by tumor-specific proliferative, cytotoxic, and cy tokine-secreting host-derived T cells. Because of the critical involvement of T cells in the antitumor immune response, we have been investigating whe ther the systemic administration of recombinant interleukin (IL)-2 can enha nce the therapeutic efficacy of TP-DC-based tumor vaccines. MATERIALS AND METHODS Immunization with TP-DC plus IL-2 administration was evaluated to determine if this combination could enhance protective immunity toward a weakly immu nogenic sarcoma (MCA-207) and a poorly immunogenic subline (D5) of the BIG melanoma and mediate therapeutic rejection of established tumors in C57BL/6 (BG) mouse models. RESULTS We have demonstrated in our murine models that the addition of IL-2 at relatively nontoxic doses can markedly augment the antitumor activity o f TP-DC-based tumor vaccine therapies against both a weakly immunogenic sar coma and a poorly immunogenic melanoma. Animals treated with the combinatio n exhibited significantly greater protection from tumor-cell challenge, sig nificantly greater regression of established tumors, and significantly long er mean survival time than with either TP-DC or IL-2 therapy alone. The mec hanism operative in vivo appears to involve the enhancement of immune T-cel l function. CONCLUSION These preclinical studies demonstrate the potential of this nove l treatment strategy and support the rationale for planned phase I/II clini cal trials of TP-DC-based vaccines plus IL-2 in patients with advanced mela noma and colorectal cancer.