Abstract 1793: 5-Fluorouracil chemotherapy acts synergistically with adoptive dendritic cell immunotherapy to induce durable anti-tumor responses in vivo

Abstract

Abstract Introduction: 5-Fluorouracil induces a form of cell death that facilitates the presentation of antigens by dendritic cells and depletes myeloid suppressor cells in vivo. The resulting immune modulation plays a substantial role in prolonging survival of mice with cancer. Our lab has previously demonstrated that a fusion of granulocyte-colony macrophage-stimulating-factor (GM-CSF) and Interleukin (IL) – 21, hereafter GIFT-21, could differentiate monocytes into a novel dendritic cell population (GIFT-21 DC). Characterization of these cells revealed a unique phenotype, with the expression of markers normally associated with both conventional and plasmacytoid dendritic cells. They are effective at cross-presenting antigens and secrete substantial amounts of CCL2, IL-6, TNF-α and IFN-α. When injected into tumor-bearing mice, they migrate to and sample from tumors in vivo, allowing them to educate CD8 T cells to recognize tumor antigens, which then significantly impeded the growth of B16 and D2F2 Neu tumors in mice. Hypothesis: We propose that 5-Fluorouracil mediated immune modulation can be combined with adoptively transferred autologous GIFT-21 DCs to treat established cancer, and lead to a synergistic anticancer immune response. Methods and Results: Twelve days following a subcutaneous tumor implantation, mice with established B16 tumors (average volume of 40mm3) were treated daily with 1.5 mg 5-Fluorouracil for 2 days and then injected on the third day with 1.5×106 syngeneic GIFT-21 DCs intraperitoneally. The treatment was repeated one week later. While 5-FU treatment alone or dendritc cell therapy alone had no significant impact on the growth of pre-established melanoma, the combination of 5-Fluorouracil with GIFT-21 DC-based immunotherapy reduced the rate of tumor growth by 75% over 5-FU and 85% over untreated mice, while eventually leading to the regression of the pre-established B16 tumors. Conclusion: These findings demonstrate how chemotherapy can be combined with immunotherapy to target cancers for which tumors antigens are unknown or ill-defined. While chemotherapy suppresses some elements of the immune system in the short term, we speculate that modulating the endogenous immunological processes secondary to chemotherapy shows promising synergy with adoptive cell therapy and is a promising avenue of future research in cancer immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1793. doi:10.1158/1538-7445.AM2011-1793