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21-06-2016 | Renal cell carcinoma | Article

Checkpoint inhibitors and other novel immunotherapies for advanced renal cell carcinoma

Authors:
Maria I. Carlo, Martin H. Voss, Robert J. Motzer

Abstract

The management of advanced renal cell carcinoma (RCC) has dramatically changed over the past decade. Therapies that target the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways have considerably expanded treatment options; however, most patients with advanced RCC still have limited overall survival. Increased understanding of the mechanisms of T cell-antigen recognition and function has led to the development of novel immunotherapies to treat cancer, chief among them inhibitors of checkpoint receptors — molecules whose function is to restrain the host immune response. In 2015, the FDA approved the first checkpoint inhibitor nivolumab for patients with advanced RCC following treatment with antiangiogenic therapy based on improved overall survival compared with the standard of care. Ongoing phase III trials are comparing checkpoint-inhibitor-based combination regimens with antiangiogenesis agents in the first-line setting. The field is evolving rapidly, with many clinical trials already testing several checkpoint inhibitors alone, in combination, or with other targeted therapies. In addition, different novel immune therapies are being investigated including vaccines, T-cell agonists, and chimeric antigen receptor T cells. Determining which patients will benefit from these therapies and which combination approaches will result in better response will be important as this field evolves.

Nat Rev Urol 2016;13: 420–431. doi:10.1038/nrurol.2016.103

Subject terms: Cancer immunotherapy • Clinical trials • Combination drug therapy • Renal cancer

Since Dr William Coley's observation in the late nineteenth century that activation of the immune system can result in tumour regression, scientists have been trying to harness the power of the immune system to treat cancer1. Renal cell carcinoma (RCC) is a natural target for testing novel immune therapies. Cytotoxic chemotherapy is generally ineffective in RCC, but cytokine-based immune therapies such as IL-2 and IFNα can be effective. For example, a small percentage of patients achieve durable remissions with high-dose IL-2 (Ref. 2). Nevertheless, such treatment is not suitable for many patients owing to a substantial incidence of high-grade adverse events, including considerable cardiopulmonary toxicity3. For many years IL-2 and IFNα were the only approved cytokine-based therapies for advanced RCC, until improved understanding of the disease biology led to the development of molecularly targeted agents. With the serial approval of several compounds directed against vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signalling, and registration trials proving these newer agents were superior to IFNα, cytokine therapies were largely replaced as standard therapies in this disease4, 5,6, 7, 8, 9, 10.

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