Biomarkers of therapeutic response in melanoma and renal cell carcinoma: potential inroads to improved immunotherapy.

The promise of biomarkers of response for melanoma and renal cell carcinoma is enormous, but to date, the potential remains largely untapped. High-dose interleukin-2 (IL-2) is the only regimen currently approved for the treatment of advanced melanoma, and it offers the prospect of prolonged disease-free survival for some patients. However, high-dose IL-2 is also one of the most toxic and difficult regimens ever developed for treatment of cancer. Hospitalization is required for supportive care. Although this regimen was approved by the US Food and Drug Administration a decade ago for treatment of stage IV melanoma on the basis of a collection of phase II trials, it has never been evaluated in a phase III trial. High-dose IL-2 is not offered at the majority of hospitals in the United States, and it is generally not even considered as therapy for most patients outside the United States. An understanding of the pathogenesis of solid tumors and the mechanism of action of therapeutic agents has provided the foundation for advancement in the treatment of breast and colorectal carcinomas. To date, such effective targeted therapy has been elusive in treatment of melanoma. For patients with melanoma who are no longer surgically curable, the prospect of treatment with high-dose IL-2 offers hope. This hope is tempered by the knowledge that of 100 patients treated, only 16 will obtain objective remission, and of these, only six will be durable beyond 2 years. The situation in adjuvant therapy for treatment of melanoma is somewhat brighter; high-dose interferon alfa-2b (IFN-2b) benefits up to 33 of 100 patients treated in the postoperative adjuvant high-risk setting. For advanced melanoma, the same agent IFN benefits only 16% of patients, a figure remarkably similar to that for IL-2. On the basis of an understanding of the mechanism of action, biomarkers of response might allow us to select certain patients who have the capacity to respond to IL-2 or IFNand treat only the 16% of the population able to derive benefit. This prospect has been an impetus to the undertaking of highthroughput analyses of potential proteomic and genomic predictors of therapeutic response. Analyses of the mechanisms of agents similar to IL-2, such as high-dose IFN, have been pursued in the study of tumor tissues before and after treatment. The impact of high-dose IFNtherapy on signal transducer and activator of transcription (STAT) 1, STAT3, and STAT5 signaling and the modulation of immunologic responses by T cells and dendritic cells of patients with nodal metastasis have been demonstrated. The study of lymphocytes in peripheral blood has also been informative. With high-dose IFN, reversals of STAT1 phosphorylation signaling defects have been found in 30% of patients with advanced disease. This fraction of patients manifesting signaling defects is remarkably similar to the fraction deriving benefit from adjuvant therapy with high-dose IFNin the postoperative adjuvant setting. Blood serum is an even more accessible but previously unmined source of potential insight into mechanism. An analysis of corollaries of response to IFN by the Hellenic Oncology Group has recently demonstrated that autoimmunity directed at endocrine and other autoantigens correlates with the therapeutic benefit of IFN, and after 3 to 12 months of therapy, the appearance of signs of autoimmunity is associated with 50-fold reduction in frequency of relapse. More recently, multiplex studies of the serum of patients treated in US Cooperative Group trials have demonstrated a correlation between long-term benefit from IFNand a profile of proinflammatory cytokines that may allow prediction of benefit before initiation of therapy. So what do we know about the subpopulation of patients responding to high-dose IL-2? Studies of tumor tissue in the context of high-dose IL-2 therapy have been undertaken using fine-needle aspiration biopsies, which have demonstrated a range of biologic effects, although these have not to date allowed the refinement of patient selection for IL-2 therapy. The pursuit of fine-needle aspiration biopsies for tumor sampling is being undertaken only at specialized centers. In this issue of Journal of Clinical Oncology, Sabatino et al report the results of a proteomic analysis of the serum of patients (most of whom had metastatic melanoma) who were treated with high-dose IL-2 using a customized, multiplex antibody-targeted protein array platform to survey expression of soluble factors associated with tumor immunobiology. Soluble factors associated with clinical responses were analyzed using a multivariate permutation test, and survival outcomes were determined using Kaplan-Meier and log-rank tests. Customized Pierce SearchLight Proteome Arrays (Thermo Fisher Scientific, Rockford, IL) were used in assays of serum before and 3 hours after the fourth dose of IL-2; 16 proteins per well were measured in standard 96 well plates spotted with different monoclonal antibodies. A sandwich enzyme-linked immunosorbent assay technique was used to generate chemiluminescent signals for calculation of the levels of each analyte. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 16 JUNE 1 2009