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
Ls. Evans et al., 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, HUM GENE TH, 10(12), 1999, pp. 1941-1951
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.