Expression of chimeric granulocyte-macrophage colony-stimulating factor/interleukin 2 receptors in human cytotoxic T lymphocyte clones results in granulocyte-macrophage colony-stimulating factor-dependent growth

Adoptive immunotherapy with ex vivo-expanded antigen-specific cytotoxic T l ymphocytes (CTLs) has been shown to clear viral infections and eliminate tu mors in murine models, Clinical trials have also reported promising data fo r the use of adoptive immunotherapy to treat cytomegalovirus (CMV) and Epst ein-Barr viral (EBV) infections in bone marrow transplant recipients. For t hese indications, the need for ex vivo-expanded CTLs is often short lived, until the immune system is reconstituted by the donor transplant. In chroni c disease settings, increased longevity of adoptively transferred CTLs and generation of memory will be necessary. The additional administration of he lper functions normally supplied by antigen-specific T helper (Th) cells wi ll probably be essential for long-term survival of adoptively transferred C TLs, Toward this goal of supplying helper functions, we transduced human CT Ls with chimeric GM-CSFR/IL-2R receptors that deliver an IL-2 signal on bin ding GM-CSF. Clones expressing the chimeric receptors proliferated in respo nse to GM-CSF. Stimulation with antigen induced GM-CSF production and resul ted in an autocrine growth loop such that the CTL clones proliferated in th e absence of exogenous cytokines. This type of genetic modification has pot ential for increasing the circulating half-life and, by extension, the effi cacy of ex vivo-expanded CTLs.