Targeting PD-1/PD-L1 in the treatment of metastatic renal cell carcinoma

Abstract

Immunostimulatory therapies have been a cornerstone of treatment for metastatic renal cell carcinoma (RCC) since the 1990s. However, the use of traditional immunotherapeutic approaches for RCC, such as high-dose interleukin-2 and interferon-α, has been limited by significant systemic toxicities and the need to deliver these therapies at centers of expertise. Furthermore, in spite of the success of these immunostimulatory therapies for some patients with RCC, it is clear that most patients fail to respond to cytokine therapy. More effective immune therapy for RCC has therefore been necessary. The interaction between programmed death-1 (PD-1, present on T cells), and one of its ligands (PD-L1, present on antigen-presenting cells and tumor cells) constitutes an immune checkpoint through which tumors can induce T-cell tolerance and avoid immune destruction. Monoclonal antibodies that disrupt the PD-1/PD-L1 interaction serve as inhibitors of this immune checkpoint, and have demonstrated favorable activity in RCC as monotherapy and in combination with other active agents. This review summarizes the current landscape of anti-PD-1/PD-L1 therapy for RCC, and highlights challenges for the future development of this promising approach.

Keywords: PD-1; PD-L1; immunotherapy; renal cell carcinoma.

Figure 1.

Interaction between the T cell and the tumor cell/antigen-presenting cell. Notes: T cells interact with antigen-presenting cells via the T-cell receptor (TCR) and major histocompatibility complex (MHC)/peptide antigen; this initial interaction is known as Signal 1. Whether the T cell is subsequently activated or inhibited depends on further interactions between proteins on the surface of these cells, termed Signal 2. Signal 2 can be T-cell-activating (as with the interaction between B7 and CD28) or T-cell-inhibitory (as with the interactions of B7/CTLA-4 and PD-1/PD-L1). Antibody blockade of either the B7/CTLA-4 (with ipilimumab or tremelimumab) or PD-1/PD-L1 (with nivolumab, pembrolizumab, MEDI0680, Atezolizumab, BMS-936559, or MEDI4736) interactions at the immune checkpoint may lead to increased activity of T cells against tumor antigens.