Genetically-modified dendritic cells serve as effective adjuvants in promoting antitumor immunity in vitro and in vivo

We have previously documented the ability of murine bone marrow (BM)-derived dendritic cells (DC) to promote prophylactic and therapeutic anti-tumor immunity when pulsed with relevant tumor-associated T-cell epitopes (Mayordomo et ai. Nature Med. 1:1297 (96), Zitvogel et al. J. Exp. Med. 183:87 (96), Celluzzi et al. J. Exp, Med. 183:283 (96)). While DCs loaded with peptides derived from tumor MHC complexes by mild acid elution were able to effectively treat animals bearing established immunogenic tumors, they promoted only an extended period of stable disease in animals bearing poorly immunogenic tumors. In order to further enhance the immunogenicity of these DC-based vaccines, we have recently engineered (gene gun) DCs to express the cytokines IL-4, IL-12, 1L-15, or IFN-alpha; factors that enhance the stimulatory capacity of DC or promote (he development of effector Tcells. In preliminary experiments, DCs enginereed to secrete 10-100 pg IL-12/1U6 cells/24h induced significantly better clinical responses in mice bearing d8-dl4 established MCA205 sarcomas than wild-type DCs in DC/tumor peptide therapy models. We are currently evaluating the therapeutic impact of DCs engineered to express combinations of these cytokines and/or tumor associated antigens.