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Improvement of cancer therapy by introducing new concepts is still urgent even though there have been major advancements lately. Immunotherapy is well on the way to becoming an established tool in the cancer treatment armory. It seems that a combination of (1) activation of immune effector cells and selective targeting of them to tumors and (2) the inhibition of immune suppression often induced by the tumor itself are necessary to achieve the therapeutic goal. The immunotoxin naptumomab estafenatox was developed in an effort to activate and target the patient's own T cells to their tumor, by fusing a superantigen (SAg) variant that activates T lymphocytes to the Fab moiety of a tumor-reactive monoclonal antibody. Naptumomab estafenatox targets the 5T4 tumor antigen, a 72-kDa oncofetal trophoblast protein expressed on many carcinomas, including renal cell carcinoma. The therapeutic effect is associated with activation of SAg-binding T cells. The SAg-binding T lymphocytes expand, differentiate to effector cells, and infiltrate the tumor. The therapeutic efficacy is most likely related to the dual mechanism of tumor cell killing: (1) direct lysis by cytotoxic T lymphocytes of tumor cells expressing the antigen recognized by the antibody moiety of the fusion protein and (2) secretion of cytokines eliminating antigen-negative tumor cell variants. Naptumomab estafenatox has been clinically tested in a range of solid tumors with focus on renal cell carcinoma. This review looks at the clinical experience with the new immunotoxin and its potential.

Patients with renal cell carcinoma (RCC) exhibit a spectrum of clinical outcomes, with some patients following an indolent clinical course and others displaying rapidly advancing disease. As evidence points to RCC being largely refractory to traditional chemotherapy and radiotherapy strategies, immunotherapeutic approaches played a dominant role in the management of metastatic RCC for a quarter of a century. Management of this challenging tumor has been revolutionized by the incorporation of molecularly targeted therapies such as inhibitors of pathways involving tyrosine kinase signaling and the mammalian target of rapamycin (mTOR). The improvements in disease stabilization and survival seen with these agents has meant that molecularly targeted therapy now forms the foundation for treating RCC and has resulted in a multitude of studies investigating similar compounds for efficacy in RCC. Despite this, the rationale for using immunomodulatory regimens remains strong and its ongoing place in this era of targeted treatments continues to pose interesting clinical questions. The challenge of maintaining durable responses from our current therapies persists and this review highlights the plethora of options now available in RCC treatment and the directions in which modern management are heading.

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.

FDA approval of the multitargeted, antiangiogenic tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib, and the serine and threonine mammalian target of rapamycin inhibitor, temsirolimus, has revolutionized the management of metastatic clear-cell renal-cell carcinoma (CC-RCC). The inability of these targeted therapies to provide durable complete responses, however, is a serious limiting factor to their clinical usefulness. Although immunotherapeutic approaches in advanced disease are increasingly regarded as a historical treatment paradigm, we propose that a fundamental understanding of immunobiology in CC-RCC can improve the selection of patients for high-dose intravenous interleukin 2 and facilitate the development of novel immunotherapeutic strategies. In our opinion, immunotherapeutic strategies have an important place in the management of advanced CC-RCC in the era of biological targeted therapy.

The last decade has seen a considerable improvement in the understanding of the biology of melanoma. Advances have come in the understanding of the importance of critical oncogenes and tumour suppressor genes, epigenetic phenomena, signalling pathways, drug resistance mechanisms, the pivotal role of the local immune system, and the importance of cell-cell and cell-matrix interactions. Many of these pathways and interactions include potentially 'drugable' targets. These developments have allowed the identification and/or design of a range of new, targeted therapies. Evaluation of these new drugs has brought a whole new series of challenges. These include identification of appropriate pre-clinical models, overcoming the redundancy in-built in complex biological systems, identification of appropriate molecular and clinical endpoints to show that the drug is hitting the target, how to combine treatments, and new toxicities. For the first time, there is the possibility of personalized treatment for melanoma patients, based on individual host and tumour characteristics. This paper discusses the range of new drugs and targets have been identified, the outcome of clinical trials, and the directions for future advances.

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.

Biological therapies are claiming a place in the routine management of some solid tumours. In this review we focus on the biological treatment of melanoma and renal-cell carcinoma, identifying the background to current practice and areas of promise that may be in routine clinical use in the near future. Melanomas and renal-cell carcinomas are particularly resistant to chemotherapy and radiotherapy and are characterised by the host immune response to the tumours. For this reason there has been particular interest in the biological therapy of these diseases. Biological therapies differ from chemotherapeutic approaches in their mechanism of action, time to response, and side-effect profiles. Although biological treatment has a long history, it is only with recent advances in immunology and molecular biology that progress has been made. In the next few years investigators expect to build on their research experience with biotherapeutic agents to provide tangible benefits for patients.

The incidence of renal cell cancer (RCC) in the elderly is increasing, yet few older patients have been enrolled in prospective clinical trials to evaluate new anti-RCC therapies. The multi-targeted tyrosine kinase inhibitor (TKI), sorafenib, is now established as a second-line treatment in advanced RCC after immunotherapy failure, and its toxicity profile is manageable. This review discusses the data on the use of anti-RCC agents in the older patient with special emphasis on sorafenib. [ABSTRACT FROM AUTHOR]

Cytoreductive nephrectomy in combination with adjuvant immunotherapy is an established treatment option for selected patients with metastatic clear-cell renal cell carcinoma (mCC-RCC). Multitargeted antiangiogenic and mammalian target of rapamycin tyrosine kinase inhibitors (TKIs) are now established treatment paradigms in patients with mCC-RCC. Given that all the recent seminal TKI trials in mCCRCC provide no evidence base for the use of cytoreductive nephrectomy in the TKI era, it is not presently clear where such a surgical approach fits into the treatment paradigm. This review summarizes the evidence for the management of mCC-RCC and outlines novel approaches to be tested within future trials if the initial proposed phase III trials in this setting, using sunitinib, are successful. Overall, two principal questions need addressing. First, is cytoreductive nephrectomy necessary in the TKI era? Second, if so,what is the most appropriate scheduling of TKI therapy with cytoreductive nephrectomy? [ABSTRACT FROM AUTHOR]

Sorafenib is a potent, orally active multitargeted kinase inhibitor. In vitro, it blocks signaling through several pathways essential for renal cell and other cancers. A large body of evidence has now accrued demonstrating the activity of sorafenib, after immunotherapy failure, in advanced renal cell cancer. Although radiological responses to single-agent sorafenib by standard response evaluation criteria in solid tumors are rare, prolongation of progression-free survival has been demonstrated and is associated with stabilization of anatomically measurable disease. Compared with other available therapies such as cytotoxic chemotherapy and high-dose intravenous interleukin-2, sorafenib is well-tolerated, and studies with this exciting new agent at earlier stages in this fatal disease are awaited. [ABSTRACT FROM AUTHOR]

Abstract: Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but a need exists to develop more effective systemic therapies. Angiogenesis has a key role in the pathophysiology of renal cell carcinoma and vascular endothelial growth factor (VEGF) is an important mediator of this process. Sunitinib, sorafenib and axitinib are new agents which belong to a class of drugs called kinase inhibitors and inhibit the VEGF, platelet-derived growth factor (PDGF) and c-KIT receptor tyrosine kinases. Temsirolimus inhibits the mammalian target of rapamycin (mTOR). All these agents have shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients generally pretreated with immunotherapy, whilst prolonged progression-free survival in a phase 3 study has been reported with sorafenib in comparison with placebo. Further phase 3 trials are recruiting and the combination of kinase inhibitors with other therapies is under investigation. [Copyright &y& Elsevier]

Abstract: Context: Until the development of novel targeted agents directed against angiogenesis and tumour growth, few treatment options have been available for the treatment of metastatic renal-cell carcinoma (mRCC). Objective: This review discusses current targeted therapies for mRCC and provides consensus statements regarding treatment algorithms. Evidence acquisition: Medical literature was retrieved from PubMed up to April 2011. Additional relevant articles and abstract reviews were included from the bibliographies of the retrieved literature. Evidence synthesis: Targeted treatment for mRCC can be categorized for the following patient groups: previously untreated patients, those refractory to immunotherapy, and those refractory to vascular endothelial growth factor (VEGF)–targeted therapy. Sunitinib and bevacizumab combined with interferon alpha are generally considered first-line treatment options in patients with favourable or intermediate prognoses. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, everolimus is now recommended. Pazopanib is a new treatment option in the first- and second-line setting (after cytokine failure). Sequential and combination approaches, and the roles of nephrectomy and tumour metastasectomy will also be discussed. Conclusions: Increasing clinical evidence is clarifying appropriate first- and second-line treatments with targeted agents for patients with mRCC. Based on phase 2 and 3 trials, a sequential approach is most promising, while combination therapy is still investigational. The role of nephrectomy in mRCC is being evaluated in ongoing phase 3 clinical trials. [Copyright &y& Elsevier]