Markedly additive anti-tumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T cell leukemia
Menée à l'aide d'un modèle murin de leucémie à lymphocytes T, cette étude évalue l'activité antitumorale d'un composé appelé YM155 en combinaison avec l'alemtuzumab
Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4+CD25+ lymphocytes caused by human T-cell lymphotropic virus I (HTLV-1). Currently, there is no accepted curative therapy for ATL. In gene expression profiling the anti-apoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). YM155, a selective small-molecule survivin suppressant, is currently in phase 2 trials in solid tumors and B-cell malignancies. In this study, we investigated the anti-tumor activity of YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P<0.001) and prolonged the survival of tumor-bearing mice (P<0.0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive anti-tumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared to monotherapy with either YM155 (P<0.001) or alemtuzumab (P<0.05). More significantly, all mice that received the combination therapy survived and were tumor-free more than 6 months after treatment. Our data supports a clinical trial of the combination of YM155 with alemtuzumab in patients with ATL. Clinicaltrials.gov NCT00061048