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Patients with metastatic renal cell cancer (mRCC) have traditionally had poor responses to systemic therapies. Recent developments in molecular biology have increased our understanding of the oncogenic processes and pathways in clear-cell mRCC. The development of drugs that target these pathways has expanded treatment options, improved prognosis and changed standard management of patients with clear-cell mRCC. Sunitinib, sorafenib and pazopanib (oral tyrosine kinase inhibitors) as well as everolimus and temsirolimus (mTOR inhibitors) and interferon with bevacizumab (an antibody to VEGF) have improved patient outcomes in large Phase III trials. These drugs have been incorporated into standard practice. Sunitinib has been adopted as first-line standard of care. Many agents are in development for treatment of mRCC, including axitinib in Phase III trials. We will review these treatments, their toxicities and how these targeted agents have impacted on mRCC.

In the past 5 years the management of metastatic renal cell carcinoma has been revolutionized by the advent of anti-angiogenic treatments, particularly the multi-targeted kinase inhibitors. This revolution has put standard and experimental immunotherapy in the shade. However, it is likely that a subset of patients with advanced kidney cancer is still best served by immunotherapy. This article summarizes promising novel immunotherapeutic techniques to identify those patients who will benefit and to optimize outcomes for patients using novel immunotherapeutic approaches.

Unlabelled: We report a patient who initially presented with an abdominal paraganglioma and subsequently metastatic papillary cell renal cancer. Genetic analysis revealed a 141 G>A (exon 2) Trp47X mutation within the succinate dehydrogenase B gene. Treatment with the novel multi-targeted tyrosine kinase inhibitor sunitinib resulted in a sustained partial response and reduced the level of the angiogenic marker PIGF., Trial Registration Number: a6181037.

Purpose: 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., 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-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)., Conclusion: 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.

Metastatic renal cell cancer (mRCC) has a long history as a disease with poor prognosis and limited therapeutic options. Immunotherapy has been the mainstay of treatment since the 1980s, and there have been a number of largely phase II studies examining various schedules of interferon-alpha and interleukin-2 based treatments. With the development of molecular targeted drugs the armentarium against mRCC has significantly expanded and cytokine treatments should be only directed at those most likely to benefit with durable remissions and prolonged survival.

Antibodies to the cell surface disaccharide galactose(alpha1,3)galactose (alphaGal) are the most prevalent natural antibodies in human serum. The anti-alphaGal immunoglobulin M-dependent activation of complement causes hyperacute rejection of organ transplants from discordant species by human recipients. It has been shown in vitro that human tumour cells transduced with the gene that synthesizes alphaGal become sensitive to human serum. A prerequisite for anti-alphaGal antibody-based therapeutic strategies is that patients with cancer have adequate serum levels of anti-alphaGal immunoglobulins and complement. The objective of this work was to measure the levels and function of anti-alphaGal immunoglobulins and complement in the serum of patients with metastatic melanoma and healthy volunteers. Serum complement levels were assayed by radial immunodiffusion. Anti-alphaGal immunoglobulin G and immunoglobulin M titres were measured by enzyme-linked immunosorbent assay. Disaccharide sugar blocking was used to investigate antibody specificity. The functional integrity of anti-alphaGal antibodies and complement was investigated in cell lysis assays. It was found that the levels of the complement components C1q, C3 and C4 and the function of the classical complement pathway were normal in metastatic melanoma patients. Anti-alphaGal antibody titres were as variable in metastatic melanoma patients as in healthy controls, and the lysis of alphaGal-expressing cells correlated with anti-alphaGal immunoglobulin M titre (P < 0.0001). Anti-alphaGal antibody titres, complement levels and overall cytolytic function in the serum of patients with metastatic melanoma were indistinguishable from those of healthy controls. There is thus nothing intrinsic to the disease that will limit anti-alphaGal-based therapeutic strategies for enhanced antigen presentation or induced cell lysis, including the mimicry of hyperacute rejection.