Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review

Abstract

Localized renal cell carcinoma (RCC) is often curable by surgery alone. However, metastatic RCC is generally incurable. In the 1990s, immunotherapy in the form of cytokines was the mainstay of treatment for metastatic RCC. However, responses were seen in only a minority of highly selected patients with substantial treatment-related toxicities. The advent of targeted agents such as vascular endothelial growth factor tyrosine kinase inhibitors VEGF-TKIs and mammalian target of rapamycin (mTOR) inhibitors led to a change in this paradigm due to improved response rates and progression-free survival, a better safety profile, and the convenience of oral administration. However, most patients ultimately progress with about 12% being alive at 5 years. In contrast, durable responses lasting 10 years or more are noted in a minority of those treated with cytokines. More recently, an improved overall survival with newer forms of immunotherapy in other malignancies (such as melanoma and prostate cancer) has led to a resurgence of interest in immune therapies in metastatic RCC. In this review we discuss the rationale for immunotherapy and recent developments in immunotherapeutic strategies for treating metastatic RCC.

Figure 1

Mechanism of action of immune checkpoint inhibitors. PD-1 is expressed on activated T cells and when it binds to its ligand PD-L1 on tumor cells leads to T cell exhaustion. CTLA-4 competes with CD28 (costimulatory T cell molecule) for B7 ligands (CD80 and CD86 that are not shown in the figure) and upon activation decreases T cell proliferation as well as activity. Blockade of CTLA-4 (by anti-CTLA-4) and PD-1 (anti-PD-1) or PD-L1 stimulates effector T cells to produce antitumor responses. Adapted by permission from Macmillan Publishers Ltd. [37], copyright (Jan 2014). PD-1: programmed death-1, PD-L1: programmed death-ligand 1, MHC: major histocompatibility complex, TCR: T cell receptor, and CTLA-4: cytotoxic T lymphocyte antigen.