Ex vivo interleukin-12-priming during CD8 ⁺ t cell activation dramatically improves adoptive t cell transfer antitumor efficacy in a lymphodepleted host

Background: Clinical application of adoptive T cell therapy has been hindered by an inability to generate adequate numbers of nontolerized, functionally active, tumor-specific T cells, which can persist in vivo. In order to address this, we evaluated the impact of interleukin (IL)-12 signaling during tumor-specific CD8 + T cell priming in terms of persistence and antitumor efficacy using an established B16 melanoma tumor adoptive therapy model. Study Design: B6 mice were injected subcutaneously with B16 melanoma tumor cells. On day 12 of tumor growth, mice were preconditioned with cyclophosphamide (4mg dose, intraperitoneally), and 1 day later were treated by adoptive transfer of tumor-specific pmel-1 CD8 + T cells primed ex vivo 3 days earlier with both IL-12 and antigen (hGP100 25-33 peptide) or antigen only. Tumors were measured biweekly, and infused donor T cells were analyzed for persistence, localization to the tumor, phenotype, and effector function. Results: Adoptive transfer of tumor-specific CD8 + T cells primed with IL-12 was significantly more effective in reducing tumor burden in mice preconditioned with cyclophosphamide compared with transfer of T cells primed without IL-12. This enhanced antitumor response was associated with increased frequencies of infused T cells in the periphery and tumor as well as elevated expression of effector molecules including granzyme B and interferon-γ (IFNγ). Conclusions: Our findings demonstrate that ex vivo priming of tumor-specific CD8 + T cells with IL-12 dramatically improves their in vivo persistence and therapeutic ability on transfer to tumor-bearing mice. These findings can be directly applied as novel clinical trial strategies. © 2012 by the American College of Surgeons.