Deple tion of Treg cells in mice stimulates T cell dependent immune rejection of melanoma xenografts and Treg cells are Axitinib supplier elevated in the lymph nodes of melanoma patients. Denileukin selleck Paclitaxel structure diftitox is a recombinant fusion protein product of diphtheria toxin and IL 2 that selectively binds to the IL 2 receptor of cells and, following internalization, inhibits protein synthesis, causing cell death. Treg cells express high levels of the alpha chain of the IL 2 receptor and a single administration of DAB/IL2 has been found by Curiel et al. to deplete Treg cells in patients with metastatic ovarian, breast or squa mous cell lung carcinomas. Furthermore, exposure of peripheral blood mononuclear cells to DAB/IL2 reduces the T cell suppressive activity of Treg cells in vitro.
Taken together, these studies suggest that DAB/IL2 may have clinical utility for the treatment of melanoma. In Inhibitors,Modulators,Libraries a prior study, Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries we examined the effect of DAB/IL2 on the peripheral blood concentration of Treg cells in 16 metastatic melanoma Inhibitors,Modulators,Libraries patients. DAB/IL2 caused a Inhibitors,Modulators,Libraries transient depletion of Treg cells that coincided with the de novo appearance of melanoma antigen specific CD8 T cells. Although the study was not designed Inhibitors,Modulators,Libraries to assess clinical efficacy, we did observe the regression of melanoma metastases in 3 patients. In order to better define the clinical activity of DAB/IL2 against melanoma and provide rationale for randomized multi center trials, we now have expanded this initial exploratory trial to include a total of 60 stage IV melanoma patients and will present herein the objective response rates and results of survival Inhibitors,Modulators,Libraries analyses.
We find Inhibitors,Modulators,Libraries that DAB/IL2 has significant clinical activity against stage IV mela noma. lack of prior exposure to chemo/immunother apy is associated with an increased response Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries rate to DAB/IL2. and patients Inhibitors,Modulators,Libraries who respond live signifi cantly longer than patients Inhibitors,Modulators,Libraries who experience progressive disease. Based Inhibitors,Modulators,Libraries on the results of this study, a new rando mized multi center clinical trial of DAB/IL2 has been initiated that will correlate Treg depletion with objective responses in chemo/immuno na ve melanoma patients.
Methods Trial design This study was a single arm, open label phase II study of DAB/IL2 undertaken from 2007 to 2010 at the James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky.
The primary objective was to determine the response rate of DAB/IL2 in stage IV metastatic melanoma patients.
selleck inhibitor A secondary the site objective was the determination of overall survival after DAB/IL2 administration. The clinical trial registration number is NCT00299689. Patient enrollment This Inhibitors,Modulators,Libraries clinical trial was approved by the University of Louisville Human Subjects Committee. Only patients with distant metastases from cutaneous, ocular, mucosal melanoma Inhibitors,Modulators,Libraries or melanoma of unknown primary free copy were eligi ble for inclusion.