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

Departments of ¹ Microbiology and Immunology, ² Surgery, and ³ Graduate Program in Immunology, and ⁴ School of Public Health, University of Michigan Medical School, Ann Arbor, Michigan; ⁵ Department of Pediatrics, M.D. Anderson Cancer Center, Houston, Texas; and ⁶ Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky

Requests for reprints: Jennifer N. MacGregor, Department of Microbiology and Immunology, University of Michigan Medical School, 1150 West Medical Center Drive, 6606 Medical Science Building II, Ann Arbor, MI 48109-0620. Phone: 734-615-9014; E-mail: jmacgreg{at}umich.edu.

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- 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- 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--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--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- via perforin-mediated cytolysis. (Cancer Res 2006; 66(9): 4913-21)