title: Phase I clinical trial combining imatinib mesylate and IL-2: HLA-DR+NK cell levels correlate with disease outcome.
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 ofOncoImmunology, 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.
authors.affiliation: 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.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.forename: Clara
authors.initials: C
authors.lastname: Locher
authors.forename: Mélanie
authors.initials: M
authors.lastname: Desbois
authors.forename: Annie
authors.initials: A
authors.lastname: Rey
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rusakiewicz
authors.forename: Vichnou
authors.initials: V
authors.lastname: Poirier-Colame
authors.forename: Patricia
authors.initials: P
authors.lastname: Pautier
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.forename: Michelle
authors.initials: M
authors.lastname: Rosenzwajg
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
keywords: NK cells; cancer; imatinib mesylate; innate immunity; interleukin-2; melanoma; regulatory T cells