title: Clinical and immunomodulatory effects of bevacizumab and low-dose interleukin-2 in patients with metastatic renal cell carcinoma: results from a phase II trial.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic Glickman Urological and Kidney Institute, Cleveland, OH, USA. Garciaj4@ccf.org
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Garcia
authors.forename: Tarek
authors.initials: T
authors.lastname: Mekhail
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.forename: Pierre
authors.initials: P
authors.lastname: Triozzi
authors.forename: Cheryl
authors.initials: C
authors.lastname: Nemec
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Bukowski
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D007376:Interleukin-2 / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007376:Interleukin-2; D000068258:Bevacizumab