Clearing up Clear Cell: Clarifying the Immuno-Oncology Treatment Landscape for Metastatic Clear Cell RCC

Abstract

Patients with advanced or malignant renal cell carcinoma at the time of diagnosis have historically had a poor prognosis. Immunonologic agents have significantly altered the therapeutic landscape and clinical outcomes of these patients. In this review, we highlight recent and upcoming clinical trials investigating the role of immunotherapies in clear cell RCC. In particular, we emphasize immunotherapy-based combinations, including immune checkpoint inhibitor (ICI) combinations, neoadjuvant, and adjuvant ICI, and ICI agents combined with anti-VEGF therapy.

Keywords: immune checkpoint inhibitors; immunotherapy; kidney cancer; renal cell carcinoma.

Figure 1

VEGF promotes many immune mediated effects that promotes tumorigenesis. VEGF upregulates immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), T regulatory cells (Treg), and M2 macrophages which promote tumor cell formation as indicated by the (+) sign. In addition, VEGF prevents the maturation of dendritic cells and reduces the effectiveness and number of CD8+ T cells by inducing PD1/PD-L1 interactions and by promoting FAS binding. Because dendritic cells and CD8+ T cells normally inhibit tumorigenesis, a (-) sign is seen adjacent to their depictions.

Figure 2

Mechanism of angiogenesis in sporadic RCC. Everolimus–inhibitor of mTOR. Sunitinib–tyrosine kinase inhibitor of VEGF. Axitinib-TKI of VEGF. Lenvatinib–multiple kinase inhibitor of VEGF. Cabozantinib–TKI of RET, MET, and VEGFR2. Bevacizumab–anti-VEGF monoclonal antibody.

Figure 3

Schema of tumor induced T-cell anergy and immuno-oncology agents. Ipilimumab–anti-CTLA4 monoclonal antibody. Nivolumab–anti-PD-1 monoclonal antibody. Pembrolizumab-anti-PD-1 monoclonal antibody. Atezolizumab-anti-PD-L1 monoclonal antibody. Avelumab-anti-PD-L1 monoclonal antibody.