Macrophage-mediated immunostimulation modulates therapeutic efficacy of interleukin-2 based chemoimmunotherapy in advanced metastatic melanoma patients

The biological mechanisms of chemoimmunotherapy efficacy in vivo have not b een fully clarified; furthermore, few data are available to predict its eff icacy on the basis of clinical and immunological pretreatment factors. In t his paper, pre- and post-treatment serum levels of cytokines (interleukin [ IL]-6, IL-10, IL-12 and neopterin) and soluble IL-2 receptors (sIL-2R), as well as circulating levels of T-cell and NK subpopulations, were analysed a ccording to clinical outcome in 66 advanced metastatic melanoma (MM) patien ts treated with subcutaneous IL-2 in association with interferon-alpha, cis platin and tamoxifen. Our purpose was to correlate the immune modifications during treatment with the clinical response and to define pretreatment fac tors with predictive value for clinical outcome. The overall response rate was 35%, with a median overall survival of 11.3 months. During treatment, r esponding patients showed a common marked increase in IL-12 (mainly release d by activated macrophages), sIL-2R and neopterin serum levels, associated with high levels of total lymphocytes and circulating natural killer lympho cytes; progressing patients were characterized by an increase in IL-6 serum levels (directly related to the increase in tumour burden). Multivariate a nalysis showed that high pretreatment IL-12 levels (P = 0.05) and, to a les ser extent, lactate dehydrogenase levels in the normal range (less than or equal to 450 U/l; P = 0.061) are independent favourable prognostic factors for survival. Our results show that macrophage activation in an immunostimu lating way either before or during treatment is associated with a better cl inical response and improved survival in advanced MM patients treated with IL-2-based chemoimmunotherapy. (C) 2000 Lippincott Williams & Wilkins.