B12
Translational studies on anti-TNF-α antibodies in Renal Cell Carcinoma (RCC)
Eva Obermueller1, Michelle Harrison2, Sue Hoare1, Ningfeng Li1, Kim Edmonds2, Robert Corringham3, Mark DeWitte3, Martin Gore1
1Centre for Cancer and Inflammation, Barts and The London School of Medicine and Dentistry, London, UK, 2Royal Marsden Hospital, London, UK, 3Centocor R&D, Inc, Malvern, PA, USA
Background
Increasing evidence links inflammation and cancer. Tumour necrosis factor-α (TNF-α is a key molecule in the inflammatory process and is elevated in malignancies, inducing a cytokine network and thus facilitating tumour growth, invasion and angiogenesis.
We previously reported that the monoclonal anti-TNF-α antibody had some clinical activity in two sequential phase II studies in patients with metastatic RCC [1].
Method and results
Analysis of plasma samples of patients treated with infliximab revealed that higher levels of TNF-α at baseline and of CCL2 during treatment correlated with progressive disease. Higher levels of TNF-α, IL-6 and CCL2 also correlated with poor survival (<12 months) after infliximab treatment. This was the first direct clinical evidence suggesting TNF-α as a therapeutic target in RCC with possible predictive and prognostic significance of plasma levels of TNF-α, IL-6 and CCL2.
TNF-α and its receptors were detected in malignant cells in RCC biopsies and RCC cell lines. To begin to understand the mechanisms of action of infliximab, we studied its effects on four RCC cell lines, two of which had a mutation in the VHL gene. This mutation is very common in RCC. Treatment of these cell lines with clinically relevant doses of infliximab had little effect on RCC cell growth or invasion, but some effect on release of the cytokines TNF-α, IL-6 and IL-8, especially in cells that had not lost the functional VHL gene.
Conclusion
We suggest that infliximab affects tumour growth through modulation of the tumour-stroma crosstalk rather than having a direct effect on the tumour cells.
References
[1] Harrison ML, Obermueller E, Maisey NR, Hoare S, Edmonds K, Li NF, Chao D, Hall K, Lee C, Timotheadou E, Charles K, Ahern R, King DM, Eisen T, Corringham R, DeWitte M, Balkwill F, Gore M: Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose, J Clin Oncol: 2007, 25:4542-4549
