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

Abstract

Adoptive immunotherapy with ex vivo-expanded antigen-specific cytotoxic T lymphocytes (CTLs) has been shown to clear viral infections and eliminate tumors in murine models. Clinical trials have also reported promising data for the use of adoptive immunotherapy to treat cytomegalovirus (CMV) and Epstein-Barr viral (EBV) infections in bone marrow transplant recipients. For these indications, the need for ex vivo-expanded CTLs is often short lived, until the immune system is reconstituted by the donor transplant. In chronic disease settings, increased longevity of adoptively transferred CTLs and generation of memory will be necessary. The additional administration of helper functions normally supplied by antigen-specific T helper (Th) cells will probably be essential for long-term survival of adoptively transferred CTLs. Toward this goal of supplying helper functions, we transduced human CTLs with chimeric GM-CSFR/IL-2R receptors that deliver an IL-2 signal on binding GM-CSF. Clones expressing the chimeric receptors proliferated in response to GM-CSF. Stimulation with antigen induced GM-CSF production and resulted in an autocrine growth loop such that the CTL clones proliferated in the absence of exogenous cytokines. This type of genetic modification has potential for increasing the circulating half-life and, by extension, the efficacy of ex vivo-expanded CTLs.