Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and XXXX effectively treats local and distant disease in association with broadly reactive Tc1-type immunity.

@entity242 @entity6026 @entity19 @entity5 @entity60 @entity1961
Dendritic cells (DCs) were adenovirally engineered to constitutively and durably secrete the potent Th1-biasing cytokines interleukin (IL)-12 (AdIL12DC) and/or @entity6026 (AdIL18DC) and evaluated for their ability to promote therapeutic antitumor immunity in @entity19 @entity242 models. Injection of either AdIL12DC or AdIL18DC into day 7 CMS4 or MethA @entity5 resulted in @entity5 rejection or slowed @entity5 growth when compared with control cohorts. Importantly, intratumoral injection with DCs engineered to secrete both IL-12 and @entity6026 ( @entity6026 ) resulted in complete and the most acute rejection of any treatment group analyzed. This strategy was also effective in promoting the regression of contralateral, untreated @entity5 . Both @entity1961 + and CD8+ T cells were required for @entity5 rejection. CD8+ splenic T cells from @entity19 treated with @entity6026 produced the highest levels of @entity60 in response to @entity5 rechallenge in vitro and displayed the broadest repertoire of Tc1-type reactivity to acid-eluted, @entity5 -derived peptides among all treatment cohorts. This apparent enhancement in cross-presentation of @entity5 -associated epitopes in vivo may result from the increased capacity of engineered DCs to kill @entity5 cells, survive @entity5 -induced apoptosis, and present immunogenic MHC/ @entity5 peptide complexes to T cells after intratumoral injection. In support of this hypothesis, cytokine gene-engineered DCs expressed higher levels of MHC and costimulatory molecules, as well as Fas ligand and membrane-bound @entity5 necrosis factor alpha, with the latter markers associated with elevated tumoricidal activity in vitro. Cytokine gene-engineered DCs appeared to have a survival advantage in situ when injected into @entity5 lesions, to be found in approximation with regions of @entity5 apoptosis, and to have the capacity to ingest apoptotic @entity5 bodies. These results support the ability of combined cytokine gene transfer to enhance multiple effector functions mediated by intralesionally injected DCs that may concertedly promote cross-priming and the accelerated immune-mediated rejection of @entity5 .
