Predicting Response to Interleukin-2 Therapy Among Patients with Renal Cell Carcinoma

Approximately one third of patients with renal cell carcinoma (RCC) will have evidence of metastasis at the time of diagnosis, and nearly 30% of patients will develop recurrence after treatment of clinically localized disease. Improved staging and treatment have increased survival for a select group of patients, but metastatic RCC still carries a poor prognosis. Immunotherapy is currently the only effective systemic treatment option for patients with metastatic disease, although response rates are modest. IL-2 is the only FDAapproved drug for metastatic RCC, although new agents are under review. Approximately 20% of patients show a clinical response to high-dose IL-2 therapy, but treatment is associated with significant morbidity and complexity of use. Clinicians must weigh the potential benefit of significant or even curative response in a minority of patients with quality-of-life considerations for patients with metastatic RCC. This common clinical scenario underscores the importance of defining patient characteristics associated with response to immunotherapy regimens. In this issue of the Journal of Immunotherapy, Upton et al present a model using the histologic and pathologic features of primary tumor specimens to select patients most likely to respond to IL-2-based immunotherapy. This study retrospectively reviewed patients enrolled in clinical trials for metastatic RCC in the Cytokine Working Group (CWG) or Beth Israel Deaconess Medical Center (BIDMC). Patients enrolled in the CWG trials received immunotherapy regimens including high-dose IL-2 6 IFNa, low-dose IL-2, or subcutaneous IL-2 combined with IFNa 6 5-flurouracil. Specimens from BIDMC were obtained from patients enrolled in various clinical trials involving IL-2 between 1997 and 2001. A total of 163 RCC primary tumor specimens were analyzed for tumor stage, histologic type, morphologic features, Fuhrman nuclear grade, tumor necrosis, and the presence of tumor infiltrating lymphocytes. The patient’s response to immunotherapy was scored as complete, partial (.50% decrease in measurable tumor), or no response. The tumor characteristics were then correlated with clinical response. Based on tumor characteristics, patients were stratified into ‘‘best prognosis,’’ ‘‘intermediate prognosis’’ and ‘‘poor prognosis’’ groups. The significant correlates with clinical response were then tested in a separate analysis of 68 tumor specimens from metastatic lesions. In this patient cohort, response to IL-2-based immunotherapy correlated with clear cell histology, presence of . 50% alveolar features, and tumor involvement of major renal vein. Response was inversely correlated with non-clear cell histology, presence of granular features, and microvascular involvement. No association with IL-2 response was seen in patients with tubular or cystic morphology, a higher proportion of sarcomatoid or rhabdoid phenotype, extensive tumor necrosis, the presence of tumor infiltrating lymphocytes, or nuclear grade. Tumor characteristics in the ‘‘best prognosis’’ category for clear cell primary RCC specimens included the absence of papillary features, more than 50% alveolar features, and the absence of granular features. ‘‘Intermediate prognosis’’ features included the presence of any alveolar features and less than 50% granular features. ‘‘Poor prognosis’’ was associated with non-clear cell histology, significant granular features, and the absence of alveolar features. For the 168 primary clear cell RCC specimens, response rates for these three groups were 39%, 19%, and 3%, respectively (P, 0.001). This predictive model was