Ex vivoCulture with Interleukin (IL)-12 Improves CD8+ T-Cell Adoptive Immunotherapy for Murine Leukemia Independent of IL-18 or IFN-γ but Requires Perforin

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Abstract
In animal models and clinical trials, adoptive transfer of activated, antigen-specific CD8+ T cells mediates tumor regression in a cell dose-dependent manner. The cytokine interleukin (IL)-12 promotes CD8+ T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-γ release. We have shown that culturing CD8+ T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Activated ovalbumin-specific CD8+ T cells cultured with IL-12, IL-18, both, or neither were assayed for antigen-specific cytokine production and cytolytic activity and adoptively transferred to C57BL/6 mice with established tumors. Maximal IFN-γ release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure. T cells cultured with IL-12 more effectively eliminated tumors, and addition of IL-18 did not further augment responses. IFN-γ-deficient CD8+ T cells showed effective antitumor activity that was enhanced by IL-12 with or without IL-18. Perforin-deficient CD8+ T cells were poor mediators of antitumor activity, though, and showed no improvement after culture with IL-12 and/or IL-18. Thus, ex vivo culture with IL-12 was sufficient to augment antigen-specific in vitro cytotoxicity and antitumor activity in vivo in an IFN-γ-independent but perforin-dependent manner. Ex vivo culture with IL-12 may improve CD8+ T-cell immunotherapy of cancer in the absence of donor cell–derived IFN-γ via perforin-mediated cytolysis. (Cancer Res 2006; 66(9): 4913-21)
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