GM-CSF may augment the graft versus leukemia effect of allogeneic transplantation Relapse of acute leukemia after allogeneic transplanta- tion remains a signiﬁcant therapeutic challenge, affecting approximately one third of all patients with acute leukemia who receive allogeneic transplantation as a curative therapy. Salvage post-transplant maneuvers have focused on utilization of second transplants, but these are limited to a minority (10% in most series) of ﬁt patients. Clinical and pre-clinical data has suggested a role for cytokine therapy in the induction of graft versus leukemia effects in the setting of post-transplant relapse (Slavin et al 1996; Cortes et al 1998; Boyer et al 2000; Mohty et al 2002; Kolb et al 2004; Li and Waller 2004). Improving the antigen-presenting capacity of leukemic blasts may lead to clinically-signiﬁcant anti-leukemic effects. The feasibility of generating DC-like leukemic antigen presenting cells upon treatment with cytokines, including GM-CSF has been demonstrated ( Santiago-Schwarz et al 1994; Mohty et al 2002). The level of co-stimulatory molecule expression on leukemic blasts has been hypothesized to play a role in the capacity of leukemic blasts to present antigen to effector cells (Vereecque et al 2000; Whiteway et al 2003). A retrospec- tive study at our institution reviewing the treatment of acute leukemia relapsed after allogeneic transplantation revealed promising results among a minority of patients treated with GM-CSF and interferon-alpha-2b (Arellano et al 2007). A prospective clinical trial at our center is currently investigating the feasibility and activity of a regimen utilizing the combina- tion of GM-CSF and interferon-alpha-2b after cytoreduction to treat acute leukemia relapsed after allogeneic transplanta- tion. Correlative studies will test the hypothesis that GM-CSF and interferon-alpha-2b act by up-regulating co-stimulatory molecules on leukemic blasts, and down-regulating regulatory T-cells leading to improved antigen presentation and durable graft versus leukemia effects (Figure 1). GM-CSF for the treatment of solid tumors Role of GM-CSF in the management of renal cell carcinoma Renal cell carcinoma (RCC) is known to be an immunogenic tumor. Interferon-alpha (IFN-alpha) has been established as the standard treatment for metastatic RCC with response rates ranging between 10 and 20%. High dose interleukin- 2 has yielded similar results, but its use has been limited by significant toxicities (Coppin et al 2005). Previous Biologics:Targets & Therapy 2008:2(1) acute leuk. IFN GM-CSF other Leukemia blasts Leukemic APC Clinical uses of GM-CSF Co-stimulatory molecules Cytokines Leukemia-specific CTL (GVL) Figure 1 GM-CSF and IFN may upregulate co-stimulatory molecule expression on leukemic blasts leading to stimulation of cytotoxic T-cells and a GVL effect. Abbreviations: APC, antigen presenting cells; GVL, graft versus leukemia; GM-CSF, granulocyte-macrophage-colony-stimulating factor; IFN, interferon; CTL, cytotoxic T lymphocyte. observations have indicated that GM-CSF can potentiate the effect of IL-2 on T-cell activation (Masucci et al 1990; Groenewegen and de Gast 1999). Subsequently multiple trials have tested the activity of GM-CSF combinations for RCC with modest results. Table 1 summarizes activity and toxici- ties of GM-CSF in the treatment of renal cell carcinoma. Verra and colleagues studied the effect of simultaneous administra- tion of low dose IL-2, IFN-alpha and GM-CSF in metastatic RCC in a phase I study and, subsequently in a multicenter phase II study, showing tolerability and promising efﬁcacy with 19% overall responses (9% CR, 10% PR) (De Gast et al 2000; Verra et al 2003). Recently, the same group conducted a phase I study of peri-operative low-dose IL-2, IFN-alpha, and GM-CSF in resectable RCC. In addition to determining the maximum tolerated dose of the cytokine combination in the peri-operative setting, the investigators studied the effects of the cytokines in the peripheral blood and at the tumor site. They found higher numbers of tumor-inﬁltrating T-cells and mature DC1 in tumors resected from patients who received peri-operative cytokines, compared to a control group of tumors resected from non-cytokine treated patients (Verra et al 2005). The advent of targeted therapy for RCC has marked a new paradigm in the treatment of this tumor (Motzer and Bukowski 2006), and further studies may ﬁnd a role for combining cytokines with the newer targeted agents. 19