Abstract
Abstract We have recently shown that intra-tumor (i.t.) injection of syngenic dendritic cells (DC) engineered to express the transcription factor Tbet (TBX21) promotes protective Type-1 T cell-mediated immunity via a mechanism that is largely interleukin (IL)-12p70-independent. Since IL-12 is a classical promoter of Type-1 immunity, the current study was undertaken to determine whether gene therapy using combined Tbet and IL-12 cDNA would yield improved anti-tumor efficacy based on the complementary/synergistic action of these biologic modifiers. Mice bearing established s.c. tumors injected with DC concomitantly expressing ectopic Tbet and IL-12 (i.e. DC.Tbet/IL12) displayed superior i.) rates of tumor rejection and extended overall survival, ii.) cross-priming of Tc1 reactive against antigens expressed within the tumor microenvironment, and iii.) infiltration of CD8+ T cells into treated tumors in association with elevated locoregional production of CXCR3 ligand chemokines. In established bilateral tumor models, i.t. delivery of DC.Tbet/IL12 into a single lesion led to slowed growth or regression at both tumor sites. Furthermore, DC.Tbet/IL12 pulsed with tumor antigen-derived peptides and injected as a therapy distal to the tumor site prevented tumor growth and activated robust antigen-specific Tc1 responses. These data support the translational use of combined Tbet and IL-12p70 gene therapy in the cancer setting. In order to target multiple gene pathways which should provide a more beneficial clinical outcome, we have begun combinational immunotherapy with DC.Tbet/IL12 and chemotherapeutic drugs targeting multiple receptor tyrosine kinases (i.e. sunitinib). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1537. doi:1538-7445.AM2012-1537
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