Phase I clinical trial combining imatinib mesylate and IL-2: HLA-DR(+) NK celllevels correlate with disease outcome.

摘要

We performed a Phase I clinical trial from October 2007 to October 2009,enrolling patients affected by refractory solid tumors, to determine the maximum tolerated dose (MTD) of interleukin (IL)-2 combined with low dosecyclophosphamide (CTX) and imatinib mesylate (IM). In a companion paper publishedin this issue of OncoImmunology, we show that the MTD of IL-2 is 6 MIU/day for 5 consecutive days, and that IL-2 increases the impregnation of both IM and of its main metabolite, CGP74588. Among the secondary objectives, we wanted to determineimmunological markers that might be associated with progression-free survival(PFS) and/or overall survival (OS). The combination therapy markedly reduced the absolute counts of B, CD4(+) T and CD8(+) T cells in a manner that wasproportional to IL-2 dose. There was a slight (less than 2-fold) increase in the proportion of regulatory T cells (Tregs) among CD4(+) T cells in response to IMplus IL-2. The natural killer (NK)-cell compartment was activated, exhibiting asignificant upregulation of HLA-DR, tumor necrosis factor-relatedapoptosis-inducing ligand (TRAIL) and CD56. The abundance of HLA-DR(+) NK cellsafter one course of combination therapy positively correlated with both PFS andOS. The IL-2-induced rise of the CD4(+):CD8(+) T-cell ratio calculated after the first cycle of treatment was also positively associated with OS. Overall, thecombination of IM and IL-2 promoted the rapid expansion of HLA-DR(+) NK cells andincreased the CD4(+):CD8(+) T-cell ratio, both being associated with clinicalbenefits. This combinatorial regimen warrants further investigation in Phase IIclinical trials, possibly in patients affected by gastrointestinal stromaltumors, a setting in which T and NK cells may play an important therapeutic role.