NK and CD8+ T cell-mediated eradication of poorly immunogenic B16-F10 melanoma by the combined action of IL-12 gene therapy and 4-1BB costimulation.

In previous reports, systemic administration of a stimulatory monoclonal antibody directed against the 4-1BB receptor had no effect on survival or tumor burden in mice inoculated with the poorly immunogenic B16-F10 melanoma. We combined IL-12 gene transfer with 4-1BB costimulation to explore a previously noted cooperative anti-tumor effect against this model tumor. We hypothesize that the innate immune response mediated by IL-12-activated natural killer (NK) cells initiates the activation of the immune system, leading to the priming of T cells, whereas 4-1BB costimulation enhances the function of primed tumor-specific T cells. The effect of the combination therapy on the growth of subcutaneous (s.c.) tumors and pulmonary metastasis was examined. The combination therapy significantly retarded the growth of subcutaneously-inoculated tumors, and 50% of tumor-bearing mice survived with complete tumor regression. In contrast, neither IL-12 gene transfer nor anti-4-1BB antibody administration alone was as effective. Enhanced CTL activity against both B16-F10 tumor cells and TRP-2-pulsed EL4 syngeneic tumor cells was observed in tumor-bearing animals treated with the combination therapy 2 weeks after treatment and, in long-term survivors from this combination therapy, at >120 days. In a pulmonary metastatic model, only the combination therapy generated significant protection against metastasis. In vivo depletion of NK or CD8(+) but not CD4(+) subsets eliminated the protective immunity. Furthermore, NK cell depletion significantly reduced both tumor-specific CTL activity and the number of tumor-specific IFN-gamma-producing cells, suggesting that this synergistic effect requires the participation of both NK and CD8(+) T cells.

Xu D ，Gu P ，Pan PY ，Li Q ，Sato AI ，Chen SH ... -  《INTERNATIONAL JOURNAL OF CANCER》

T cell activation with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer.

Martinet O ，Divino CM ，Zang Y ，Gan Y ，Mandeli J ，Thung S ，Pan PY ，Chen SH ... -  《GENE THERAPY》

Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation.

Chen SH ，Pham-Nguyen KB ，Martinet O ，Huang Y ，Yang W ，Thung SN ，Chen L ，Mittler R ，Woo SL ... -  《MOLECULAR THERAPY》

Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation.

Kim JA ，Averbook BJ ，Chambers K ，Rothchild K ，Kjaergaard J ，Papay R ，Shu S ... -  《CANCER RESEARCH》

Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines.

Ito F ，Li Q ，Shreiner AB ，Okuyama R ，Jure-Kunkel MN ，Teitz-Tennenbaum S ，Chang AE ... -  《CANCER RESEARCH》