At the time of the first interim analysis, 55 and 53 patients had been enrolled into the DTIC- and DC-arm, respectively
At the time of the first interim analysis, 55 and 53 patients had been enrolled into the DTIC- and DC-arm, respectively. (Thomson)D IFN1707.6 versus 8.8NS[20]1994 (Bajetta)D IFNa24211 versus 11 versus 13NS[21]1998 (Falkson)D GW843682X versus D/IFN versus D/T versus D/IFN/T25810 versus 9 versus 8 versus 9.5NS[22]2000 (Middleton)D/IFN versus DCBT1056.5 versus 6.5NS[23]2001 (Young)D IFN617.2 versus 4.8NS[24]2005 (Kaufmann)TMZ IFN2828.4 versus 9.7NS[25]2005 (Vuoristo)D/nIFN versus DCBT/rIFN versus D/rIFN versus DCBT/rIFN10811 versus 10 versus 9 versus 7.5NS[26]1993 (Sparano)IL-2 IFN8510.2 versus 9.7NS[15]2002 (Agarwala)IL-2 histamine3059.1 versus 8.2NS[27]1997 (Keilholz)IL-2/IFN C1339 versus 9NS[28]1998 (Johnston)CDBT IFN/IL-2655.5 versus 5.0NS[29]1999 (Dorval)C/IL-2 IFN11710.4 versus 10.9NS[30]1999 (Rosenberg)CDT IFN/IL-210215.8 versus 10.7 0.06[31]2001 (Hauschild)D/IFN IL-229011 versus 11NS[32]2002 (Eton)CVD IFN/IL-21839.2 versus 11.9 0.06[33]2002 (Atzpodien)D/B/C/T IFN/IL-212413 versus 12NS[34]2002 (Ridolfi)CVD IFN/IL-21769.5 versus 11.0NS[35]2005 (Keilholz)CD/IFN IL-23639 versus 9NS[36]2006 (Bajetta)CVD IFN/IL-213912 versus 11NS[37]2008 (Atkins)CVD IFN/IL-24168.7 versus 8.4NS[38] Open in a separate window aDose 3 or 9 MIU. D, dacarbazine; C, cisplatin; V, vinblastine; B, BCNU (carmustine); T, tamoxifen; IFN, interferon ; IL-2, interleukin-2; TMZ, temozolomide; NS, not significant; n, natural; r, recombinant. interleukins 15 and 21 The common GW843682X cytokine receptor -chain is a critical component of the receptors for IL-2, 4, 7, 9, 15 and 21. IL-21 and IL-15 have sequence homology with IL-2. IL-21 is produced by activated CD4+ T cells and NK-cells. IL-21 has pronounced effects on B cell differentiation and antibody production, mostly via CD40. Furthermore, activation of the IL-21 receptor leads to multiple effects on T cells, including proliferation, differentiation and activation of cytokine and chemokine production. IL-21 has effects on both CD8+ T cells and CD4+ T cells, and synergises with IL-15 in inducing an optimal and sustained antigen-specific CD8+ T cell response [39]. In contrast to IL-2, IL-21 does not enhance the proliferation of T regulatory cells. IL-21 may therefore promote autoimmunity and consequently also antitumour immunity in cancer patients. IL-15 was initially identified based on its ability to stimulate proliferation of IL-2-dependent T cell lines in the presence of neutralising anti-IL-2 antibodies. IL-15 mediates functions very similarly to IL-2, as these two cytokines share receptor -subunits. However, distinctly different -subunits lead to differences in immune function [40]. IL-21 is being investigated in clinical phase I/II studies as a single drug in patients with metastatic melanoma, and recent reports indicate that the GW843682X treatment is biologically active and well tolerated [41, 42]. monoclonal antibodies anti-cytotoxic T lymphocyte-associated antigen 4 Activation or priming of na?ve T cells requires recognition of the antigen by the T cell receptor (TCR) and provision of co-stimulatory signals. The engagement of the molecule B7 on the antigen-presenting cell with its ligand CD28 on the T cell launches a signalling cascade that is required for full T cell activation [43]. GW843682X Following antigen stimulation of the T cell, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) receptors are up-regulated and move to the cell surface. These receptors have greater affinity for B7 than CD28, and their binding induces an inhibitory signal that down-regulates T cell activation in response to a stimulus. CTLA-4 serves as a natural breaking mechanism that returns T cells EPSTI1 to homeostasis following an immune response; it controls the duration and intensity of the immune response. Monoclonal antibodies that bind to CTLA-4 can block the interaction between B7 and CTLA-4. Inhibition of this negative switch may break peripheral tolerance to self-tissues and induce antitumour responses [44]. Two fully human IgG monoclonal antibodies recognising CTLA-4, ipilimumab (MDX-010) and tremelimumab (CP-675,206), have been tested, alone or in combination, in numerous phase II trials and in four phase III trials. Comprehensive reviews were recently published on targeting the CTLA-4 receptor as a strategy for melanoma treatment [45, 46], and on clinical development of ipilimumab [47] and tremelimumab [48]. ipilimumab Activity of ipilimumab in patients with metastatic melanoma was examined alone, in combination with chemotherapy or vaccines and in various dose regimens. In a randomised.