PD-1/PD-L1 inhibitors-based treatment for advanced renal cell carcinoma: Mechanisms affecting efficacy and combination therapies

Abstract

With the widespread use of PD-1/PD-L1 monoclonal antibodies (mAbs) in the treatment of multiple malignant tumors, they were also gradually applied to advanced renal cell carcinoma (aRCC). Nowadays, multiple PD-1/PD-L1 mAbs, such as nivolumab, avelumab, and pembrolizumab, have achieved considerable efficacy in clinical trials. However, due to the primary, adaptive, and acquired resistance to these mAbs, the efficacy of this immunotherapy is not satisfactory. Theories also vary as to why the difference in efficacy occurs. The alterations of PD-L1 expression and the interference of cellular immunity may affect the efficacy. These mechanisms demand to be revealed to achieve a sustained and complete objective response in patients with aRCC. Tyrosine kinase inhibitors have been proven to have synergistic mechanisms with PD-1/PD-L1 mAb in the treatment of aRCC, and CTLA-4 mAb has been shown to have a non-redundant effect with PD-1/PD-L1 mAb to enhance efficacy. Although combinations with targeted agents or other checkpoint mAbs have yielded enhanced clinical outcomes in multiple clinical trials nowadays, the potential of PD-1/PD-L1 mAbs still has a large development space. More potential mechanisms that affect the efficacy demand to be developed and transformed into the clinical treatment of aRCC to search for possible combination regimens. We elucidate these mechanisms in RCC and present existing combination therapies applied in clinical trials. This may help physicians' select treatment options for patients with refractory kidney cancer.

Keywords: PD-1; PD-L1 inhibitor; advanced renal cell carcinoma; cellular immunity; combination therapy; fundamental mechanisms.