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Oncoimmunology. 2013 Feb 1;2(2):e23080.

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

Author information

1
Institut de Cancérologie Gustave Roussy; Villejuif, France ; Centre d'Investigation Clinique Biothérapie CICBT 507; Institut de Cancérologie Gustave Roussy; Villejuif, France ; Unité de Thérapie Cellulaire; Institut de Cancérologie Gustave Roussy; Villejuif, France ; Institut National de la Santé et de la Recherche Médicale; U1015; Institut de Cancérologie Gustave Roussy; Villejuif, France.

Abstract

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 dose cyclophosphamide (CTX) and imatinib mesylate (IM). In a companion paper published in 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 determine immunological 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 was proportional 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 IM plus IL-2. The natural killer (NK)-cell compartment was activated, exhibiting a significant upregulation of HLA-DR, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD56. The abundance of HLA-DR+ NK cells after one course of combination therapy positively correlated with both PFS and OS. 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, the combination of IM and IL-2 promoted the rapid expansion of HLA-DR+ NK cells and increased the CD4+:CD8+ T-cell ratio, both being associated with clinical benefits. This combinatorial regimen warrants further investigation in Phase II clinical trials, possibly in patients affected by gastrointestinal stromal tumors, a setting in which T and NK cells may play an important therapeutic role.

KEYWORDS:

NK cells; cancer; imatinib mesylate; innate immunity; interleukin-2; melanoma; regulatory T cells

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