Systemic administration of interleukin 2 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines.
We have reported previously that murine bone marrow-derived dendritic cells (DC) pulsed with whole tumor lysates can mediate potent antitumor immune responses both in vitro and in vivo. Because successful therapy was dependent on host immune T cells, we have now evaluated whether the systemic administration of the T cell stimulatory/growth promoting cytokine interleukin-2 (IL-2) could enhance tumor lysate-pulsed DC-based immunizations to further promote protective immunity toward, and therapeutic rejection of, syngeneic murine tumors. In three separate approaches using a weakly immunogenic sarcoma (MCA-207), the systemic administration of nontoxic doses of recombinant IL-2 (20,000 and 40,000 IU/dose) was capable of mediating significant increases in the potency of DC-based immunizations. IL-2 could augment the efficacy of tumor lysate-pulsed DC to induce protective immunity to lethal tumor challenge as well as enhance splenic cytotoxic T lymphocyte activity and interferon-gamma production in these treated mice. Moreover, treatment with the combination of tumor lysate-pulsed DC and IL-2 could also mediate regressions of established pulmonary 3-day micrometastases and 7-day macrometastases as well as established 14- and 28-day s.c. tumors, leading to either significant cure rates or prolongation in overall survival. Collectively, these findings show that nontoxic doses of recombinant IL-2 can potentiate the antitumor effects of tumor lysate-pulsed DC in vivo and provide preclinical rationale for the use of IL-2 in DC-based vaccine strategies in patients with advanced cancer.
Department of Surgery, 1520 MSRB-I, University of Michigan Medical Center, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0666, USA.
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Shimizu
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Fields
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Giedlin
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Mulé
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D019496:Cancer Vaccines; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000556:secondary* / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D019496:Cancer Vaccines; D007376:Interleukin-2; D011994:Recombinant Proteins; D007371:Interferon-gamma