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Natural Killer Cell IFN- Levels Predict Long-term Survival with Imatinib Mesylate Therapy in Gastrointestinal Stromal Tumor–Bearing Patients

¹ Institut National de la Santé Et de la Recherche Médicale (INSERM), Unit U805 "Tumor immunology and immunotherapy," ² Center of Clinical Investigations CIC Biothérapie CBT507, Departments of ³ Statistics, ⁴ Medicine, Dermatology Unit, and ⁵ Medicine, Institut Gustave Roussy, Villejuif, France; ⁶ Department of Medicine, Centre Léon Bérard, Lyon, France; ⁷ Department of Pathology and INSERM U602, Hôpital Ambroise Paré, Boulogne, France; and ⁸ Faculté Paris Sud-Université Paris XI, Kremlin-Bicêtre, France

Requests for reprints: Laurence Zitvogel, Institut National de la Sante et de la Recherche Medicale U805, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. Phone: 33-1-42-11-50-41; Fax: 33-1-42-11-60-94; E-mail: zitvogel{at}igr.fr.

Key Words: GIST • imatinib mesylate • NK cells

Clinical outcomes of gastrointestinal stromal tumor (GIST)–bearing patients treated with imatinib mesylate (IM) are variable. Other than the site of mutation within the c-kit gene, prognostic features of GIST remain undefined. IM can exhibit off-target effects such as triggering natural killer (NK) cell activity. We addressed whether NK cell functions could predict long term survival with IM. NK cell functions were followed up in 77 GIST patients enrolled onto two phase III trials. "Immunologic responders" were defined as patients whose NK cell IFN- values after 2 months of IM were higher than or equal to the baseline value at entry into the trial. The prognostic effect of IFN- on progression-free survival was assessed by a Wald test in a Cox regression analysis using the landmark method and stratified by trial and on the c-kit mutational status. Fifty-six patients were evaluable for the NK cell IFN- responses at baseline and 2 months. Their median follow-up for progression-free survival was 3.7 years. Thirty-four of 56 patients were immunologic responders to IM. In the Cox regression analysis, immunologic responders possessed a hazard ratio of progression or death equal to 0.29 (95% confidence interval, 0.12–0.70; P = 0.006) compared with nonresponders. Kaplan-Meier 2-year survival estimates were 85% for immunologic responders and 50% for nonresponders. Moreover, the immunologic response added prognostic value to the c-kit mutation. The NK cell IFN- production after 2 months of treatment could be considered an independent predictor of long term survival in advanced GISTs treated with IM. [Cancer Res 2009;69(8):3563–9]