IL-15 and IL-2 possess similar properties, including the ability to induce T cell proliferation. However, whereas IL-2 can promote apoptosis and limit CD8 ؉ memory T cell survival and proliferation, IL-15 helps maintain a memory CD8 ؉ T cell population and can inhibit apoptosis. We sought to determine whether IL-15 could enhance the in vivo function of tumor͞self-reactive CD8 ؉ T cells by using a T cell receptor transgenic mouse (pmel-1) whose CD8 ؉ T cells recognize an epitope derived from the self͞melanoma antigen gp100. By removing endogenous IL-15 by using tumor-bearing IL-15 knockout hosts or supplementing IL-15 by means of exogenous administration, as a component of culture media or as a transgene expressed by adoptively transferred T cells, we demonstrate that IL-15 can improve the in vivo antitumor activity of adoptively transferred CD8 ؉ T cells. These results provide several avenues for improving adoptive immunotherapy of cancer in patients.

Although immunotherapy based on the adoptive transfer of tumor-specific T lymphocytes has been shown to result in dramatic clinical responses in some patients, the relatively low levels of engraftment and persistence of the adoptively transferred cells may limit these responses in many patients. In an attempt to develop strategies for prolonging the survival of adoptively transferred T cells, we have carried out studies in which T cells obtained from healthy donors as well as tumor-specific T cells were transduced with a retrovirus expressing the human Bcl-2 gene. Our results indicate that these transduced T cells overexpress Bcl-2, are resistant to death, and have a survival advantage following interleukin-2 withdrawal compared with control T cells transduced with a retrovirus expressing green fluorescent protein. Tumor-specific T cells overexpressing Bcl-2 maintained their ability to specifically recognize and respond to target cells. Furthermore, we show that adoptive immunotherapy of an established B16 tumor can be significantly enhanced by overexpressing Bcl-2 in melanoma-specific T-cell receptor transgenic T cells. Our data suggest that adoptive immunotherapy approaches to the treatment of cancer patients may be enhanced using Bcl-2-modified tumorreactive T cells. (Cancer Res 2005; 65(5): 2001-8)