title: Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose.
abstract: OBJECTIVE
  Tumor necrosis factor alpha (TNF-alpha) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti-TNF-alpha monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC.
  
  
  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-alpha, CCL2, and interleukin-6 (IL-6) were measured before and during treatment.
  
  
  RESULTS
  TNF-alpha 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-alpha at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-alpha, IL-6, and CCL2 and poor survival (< 12 months).
  
  
  CONCLUSIONS
  This is the first direct clinical evidence suggesting that TNF-alpha may be a therapeutic target in RCC. Plasma levels of TNF-alpha, IL-6, and CCL2 may have predictive and prognostic significance.
authors.affiliation: Department of Medicine, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Harrison
authors.forename: Eva
authors.initials: E
authors.lastname: Obermueller
authors.forename: Nick R
authors.initials: NR
authors.lastname: Maisey
authors.forename: Susan
authors.initials: S
authors.lastname: Hoare
authors.forename: Kim
authors.initials: K
authors.lastname: Edmonds
authors.forename: Ningfeng F
authors.initials: NF
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Chao
authors.forename: Kate
authors.initials: K
authors.lastname: Hall
authors.forename: Chooi
authors.initials: C
authors.lastname: Lee
authors.forename: Eleni
authors.initials: E
authors.lastname: Timotheadou
authors.forename: Kellie
authors.initials: K
authors.lastname: Charles
authors.forename: Roger
authors.initials: R
authors.lastname: Ahern
authors.forename: D Mike
authors.initials: DM
authors.lastname: King
authors.forename: Tim
authors.initials: T
authors.lastname: Eisen
authors.forename: Robert
authors.initials: R
authors.lastname: Corringham
authors.forename: Mark
authors.initials: M
authors.lastname: DeWitte
authors.forename: Frances
authors.initials: F
authors.lastname: Balkwill
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
mesh_terms: D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000097:blood; D005260:Female; D006801:Humans; D000069285:Infliximab; D015850:Interleukin-6 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab