Bcl-2 Over-Expression and Genetic Manipulation of T Cells Provides Tumor Specificity and Enhanced Resistance to Apoptosis In Vitro

ABSTRACT

Adoptive immunotherapy using T cells has produced some encouraging clinical responses, but deficiencies resulting from a frequent lack of tumor specificity and poor survival of these cells has limited the widespread application of this approach. We used a chimeric receptor gene specific for erbB2 in T cells with genetic resistance to apoptosis to address these deficiencies. Expression of the chimeric receptor was found to be equivalent in T cells from bcl-2 transgenic-, lpr- and wild-type C57BL/6 mice. Furthermore, T cells from each mouse strain secreted similar amounts of IFN-γ in response to erbB2, and lysed erbB2⁺ tumor cells to a similar degree. Interestingly, we demonstrated that erbB2-specific T cells from Bcl-2 transgenic mice have enhanced expansion in vitro compared to T cells from C57BL/6 and Lpr mice. In addition, transduced T cells from Bcl-2 transgenic mice demonstrated increased resistance to apoptosis following activation or cytokine withdrawal, when compared to Lpr and BL/6 cells.