Clinical and immunomodulatory effects of bevacizumab and low-dose interleukin-2 in patients with metastatic renal cell carcinoma: results from a phase II trial.

OBJECTIVE Low-dose interleukin-2 (IL-2) is a historical treatment for metastatic renal cell carcinoma (mRCC). Increased vascular endothelial growth factor (VEGF) levels inhibit dendritic cell (DC) differentiation and augment production of immunosuppressive regulatory T (Treg) cells. Bevacizumab is an antibody that binds to VEGF, has activity in mRCC and may augment the anti-tumour immune effects of IL-2. To determine the clinical and immunomodulatory effects of this combination, a prospective, phase II trial of bevacizumab plus low-dose IL-2 was conducted. PATIENTS AND METHODS Patients with untreated mRCC received bevacizumab (10 mg/kg i.v. every 2 weeks) and IL-2 (125 000 units/kg/day subcutaneously from Monday to Friday for 6 consecutive weeks followed by a 2-week rest period). Endpoints included progression-free survival, Response Evaluation Criteria in Solid Tumors-defined objective response rate, immunomodulatory effects and safety. RESULTS Between January 2005 and September 2007, twenty-six patients with untreated mRCC were enrolled. The median progression-free survival was 9.6 months (95% CI, 4.1-16.9 months) The objective response rate was 15% and an additional 38% of patients had tumour burden reduction of < 30%. Grade 3 constitutional adverse events (fatigue, fever/ chills) and neutropenia were observed in 42% and 12% of patients, respectively. Peripheral blood CD1c ⁺ myeloid and CD303 ⁺ plasmacytoid DC increased during treatment as did IL-8 levels and CD4 ⁺ CD25 ⁺ FoxP3 ⁺ Treg cells. No changes in T helper type 1/2- associated cytokines were observed. CONCLUSION Bevacizumab plus low-dose IL-2 has modest clinical activity in mRCC. Toxicity was largely IL-2 related without enhancement of bevacizumab-related toxicity. Biological data indicate inhibition of VEGF levels and increase of immunosuppressive Treg cells without an effect on DC activation. [ABSTRACT FROM AUTHOR]