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

Dendritic cells (DC) can elicit potent immune responses to tumors through their 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 challenges as well as to treat established growing tumors at skin and organ sites. The antitumor effects elicited by TP-DC-based vaccines in vivo have been shown to be mediated by tumor-specific proliferative, cytotoxic, and cytokine-secreting host-derived T cells. Because of the critical involvement of T cells in the antitumor immune response, we have been investigating whether the systemic administration of recombinant interleukin (IL)-2 can enhance the therapeutic efficacy of TP-DC-based tumor vaccines.

Immunization with TP-DC plus IL-2 administration was evaluated to determine if this combination could enhance protective immunity toward a weakly immunogenic sarcoma (MCA-207) and a poorly immunogenic subline (D5) of the B16 melanoma and mediate therapeutic rejection of established tumors in C57BL/6 (B6) mouse models.

We have demonstrated in our murine models that the addition of IL-2 at relatively nontoxic doses can markedly augment the antitumor activity of TP-DC-based tumor vaccine therapies against both a weakly immunogenic sarcoma and a poorly immunogenic melanoma. Animals treated with the combination exhibited significantly greater protection from tumor-cell challenge, significantly greater regression of established tumors, and significantly longer mean survival time than with either TP-DC or IL-2 therapy alone. The mechanism operative in vivo appears to involve the enhancement of immune T-cell function.

These preclinical studies demonstrate the potential of this novel treatment strategy and support the rationale for planned phase I/II clinical trials of TP-DC-based vaccines plus IL-2 in patients with advanced melanoma and colorectal cancer.