Tumor Necrosis Factor α As a New Target for Renal Cell Carcinoma: Two Sequential Phase II Trials of Infliximab at Standard and High Dose

Abstract

Purpose: Tumor necrosis factor α (TNF-α) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti–TNF-α monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC. Patients and Methods: Patients progressing after cytokine therapy were treated with intravenous infliximab as follows: study 1 (19 patients), 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; study 2 (18 patients), 10 mg/kg at weeks 0, 2, and 6, and then every 4 weeks. Treatment continued until disease progression (PD). Response was assessed according to Response Evaluation Criteria in Solid Tumors. Plasma levels of TNF-α, CCL2, and interleukin-6 (IL-6) were measured before and during treatment. Results: TNF-α and its receptors were detected in malignant cells in RCC biopsies. In study 1, three patients (16%) achieved partial response (PR) and three patients (16%) achieved stable disease (SD). Median duration of response (PR + SD) was 7.7 months (range, 5.0 to 40.5+ months). In study 2, 11 patients (61%) achieved SD. Median duration of response was 6.2 months (range, 3.5 to 24+ months). One patient developed grade 3 hypersensitivity and another died as a result of pulmonary infection/sepsis. Enzyme-linked immunosorbent assay analysis of plasma revealed that higher levels of TNF-α at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-α, IL-6, and CCL2 and poor survival (< 12 months). Conclusion: This is the first direct clinical evidence suggesting that TNF-α may be a therapeutic target in RCC. Plasma levels of TNF-α, IL-6, and CCL2 may have predictive and prognostic significance.