Interleukin-2: Developing additional cytokine gene therapies using fibroblasts or dendritic cells to enhance tumor immunity

PURPOSE Recombinant interleukin (IL)-2 administration can mediate regression of sol id tumors in patients with melanoma and renal cell carcinoma. A better unde rstanding of the mechanisms of IL-2-mediated antitumor effects has led to t he investigation of novel immunotherapeutic approaches. The rationale for t hese immunotherapeutic approaches and the results of preliminary clinical s tudies are presented. PATIENTS AND METHODS The therapeutic potential of dendritic cells and the role of FLT3 ligand, a potent hematopoietic growth factor, was investigated in a variety of precl inical models. In addition, a clinical study with autologous dendritic cell s pulsed with synthetic melanoma peptides derived from the MART1/ Melan A, gp100, and tyrosinase proteins was conducted. Twenty-eight human leukocyte antigen (HLA)-A2+ melanoma patients received an average of 10(6) dendritic cells a week for 4 weeks. RESULTS In a murine liver metastases model, FLT3 ligand administration alone or in combination with IL-12 or IL-2 had significant antitumor effects and result ed in significant infiltration of the tumor border by lymphocytes and dendr itic cells, which was associated with an increased number of apoptotic figu res. Administration of melanoma peptide-pulsed dendritic cells to 28 patien ts with advanced metastatic melanoma produced a complete response in two pa tients and a partial response in one. Significant infiltration of T cells a nd dendritic cells into melanoma lesions was observed. CONCLUSION These studies confirm the feasibility of immunotherapeutic approaches using dendritic cells and FLT3 ligand and demonstrate their potential antitumor activity. These approaches may be effective for patients with metastatic me lanoma and other solid tumors and will likely be used to improve the effica cy of IL-2-based immunotherapy.