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

Michelle L. Harrison, Eva Obermueller, Nick R. Maisey, Susan Hoare, Kim Edmonds, Ningfeng F. Li, David Chao, Kate Hall, Chooi Lee, Eleni Timotheadou, Kellie Charles, Roger Ahern, D. Mike King, Tim Eisen, Robert Corringham, Mark DeWitte, Frances Balkwill, Martin Gore

From the Department of Medicine, Royal Marsden Hospital; Centre for Translational Oncology, Institute of Cancer and the CR-UK Clinical Centre; Queen Mary's School of Medicine and Dentistry; Department of Clinical Oncology, Royal Free Hospital; Institute of Cancer Research, London, United Kingdom; and Centocor R&D Inc, Malvern, PA

Address reprint requests to Martin Gore, PhD, FRCP, Department of Medicine, Royal Marsden Hospital, Fulham Rd, London SW3 6JJ, United Kingdom; e-mail: martin.gore{at}rmh.nhs.uk

Purpose Tumor necrosis factor (TNF-) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti–TNF- 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-, CCL2, and interleukin-6 (IL-6) were measured before and during treatment.

Results TNF- 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- at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-, IL-6, and CCL2 and poor survival (< 12 months).

Conclusion This is the first direct clinical evidence suggesting that TNF- may be a therapeutic target in RCC. Plasma levels of TNF-, IL-6, and CCL2 may have predictive and prognostic significance.

Supported by Centocor R&D Inc (F.B.).

M.L.H. and E.O. contributed equally to this work.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology Meeting, June 5-8, 2004, New Orleans, LA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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