Generation of monocyte-derived dendritic cells from patients with renal cell cancer: Modulation of their functional properties after therapy with biological response modifiers (IFN-alpha plus IL-2 and IL-12)

The combination of interferon-alpha (IFN-alpha) plus interleukin (IL-2) has been accepted in the treatment of metastatic renal cell carcinoma (MRCC), whereas vaccines based on IL-12 or dendritic cells (DCs) are still being in vestigated. Here the authors analyzed 1) the feasibility to generate functi onal monocyte-derived DCs (MDDCs) from patients treated with biological res ponse modifiers (BRMs) who have MRCC, 2) the phenotypic modulations of thes e MDDCs during BRM treatment. Eight and 13 MRCC patients received IL-2 plus IFN-alpha or IL-12 immunotherapy, respectively. The adherent fraction of m ononuclear cells from patients' blood drawn before, during, and after immun otherapy was incubated in clinically approved culture medium supplemented w ith 5% autologous serum, rhu granulocyte macrophage colony-stimulating fact or, and rhuIL-4 for a week. At day 7 or 8 of culture, floating cells were e xamined in flow cytometric and functional assays (alloreactivity, prolifera tion assays in the presence of tetanus toroid or tumor peptides, IL-12 secr etion). In all patients except two, MDDCs could be generated but at a lower rate compared with healthy volunteers. Morphologic and phenotypical analys es revealed immature DCs with low levels of CD1a or CD83 expression through out therapy with BRMs. Capacities in mixed leukocyte reactions were similar to those of healthy volunteers and stable during immunotherapy, whereas pr esentation of major histocompatibility complex class II tetanus toroid pept ide complexes was slightly enhanced during and after IL-12 therapy. IL-12 e xpression levels under IFN-gamma and CD40L stimulation were significantly l ower in MDDC cultures from patients with MRCC compared with healthy volunte ers. Overall, peripheral blood mononuclear cells from a cohort of 21 patien ts with metastatic disease who were treated with BRMs maintained their abil ity to differentiate into functional MDDCs with no selective quantitative o r qualitative advantage.