Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose.
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.
Harrison
Michelle L
ML
Department of Medicine, Royal Marsden Hospital, London, United Kingdom.
Obermueller
Eva
E
Maisey
Nick R
NR
Hoare
Susan
S
Edmonds
Kim
K
Li
Ningfeng F
NF
Chao
David
D
Hall
Kate
K
Lee
Chooi
C
Timotheadou
Eleni
E
Charles
Kellie
K
Ahern
Roger
R
King
D Mike
DM
Eisen
Tim
T
Corringham
Robert
R
DeWitte
Mark
M
Balkwill
Frances
F
Gore
Martin
M
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*
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