Human gammadelta T cells as mediators of chimaeric-receptor redirected anti-tumour immunity

Human peripheral blood gammadelta T cells (Vgamma9(+) Vdelta2(+)) can be selectively expanded in vivo by the systemic administration of aminobisphosphonates without prior antigen priming. To assess the potential of human gammadelta T cells to serve as effector cells of specific anti-tumour immunity, we expanded peripheral blood-derived gammadelta T cells and transduced them with recombinant retrovirus encoding G(D2)- or CD19-specific chimaeric receptors. Flow cytometric analysis of T cells from four individual donors cultured in the presence of zoledronate at day 14 of culture showed selective enrichment of the gammadelta T cell population (Vgamma9(+) Vdelta2(+) CD3(+) CD4(-) CD8(-)) to 73-96% of total CD3(+) T cells. Retroviral gene transfer resulted in chimaeric receptor surface expression in 73 +/- 12% of the population. Transduced gammadelta T cells efficiently recognized antigen-expressing tumour cell targets, as demonstrated by target-specific upregulation of CD69 and secretion of interferon-alpha. Moreover, transduced gammadelta T cells efficiently and specifically lysed the antigen-expressing tumour targets. They could be efficiently expanded in vitro and maintained in culture for prolonged periods. Zoledronate-activated human gammadelta T cells expressing chimaeric receptors may thus serve as potent and specific anti-tumour effector cells. Their responsiveness to stimulation with aminobisphosphonates may enable the selective re-expansion of adoptively transferred T cells in vivo, permitting long lasting anti-tumour immune control.