PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence

Abstract

Renal cell carcinoma (RCC) is the most common primary malignant tumor of the kidney in adults, representing approximately 4% of all adult cancers in the United States. Metastatic RCC is poorly responsive to conventional cytotoxic chemotherapies but can be sensitive to T-cell-directed immunotherapies such as interferon-α or interleukin-2. Despite recent progress in the application of antiangiogenic "targeted therapies" for metastatic RCC, high-dose interleukin-2 remains an appropriate first-line therapy for select patients and is associated with durable complete remissions in a small fraction of treated patients. Thus, advanced RCC provides a unique opportunity to investigate the requirements for effective antitumor immunotherapy. Accumulating evidence suggests that resistance mechanisms exploited by RCC and other tumor types may play a dominant role in limiting the effectiveness of tumor-reactive adaptive immune responses. Expression of the inhibitory coreceptor programmed cell death-1 (PD-1) on tumor-infiltrating lymphocytes within RCC tumors, as well as the expression of the PD-1 ligand (PD-L1) on RCC tumor cells, are strong negative prognostic markers for disease-specific death in RCC patients. Monoclonal antibodies targeting either PD-1 or PD-L1 have now entered clinic trials and have demonstrated promising antitumor effects for refractory metastatic RCC. This review summarizes the results of published and reported studies of PD-1- and PD-L1-targeted therapies enrolling patients with advanced RCC, focusing on key safety, toxicity, and efficacy end points. Prospects for advanced phase clinical testing and novel therapy combinations with PD-1- and PD-L1-targeted agents are discussed.

Keywords: PD-1; PD-L1; T-lymphocyte; immune checkpoint; immunotherapy; renal cell carcinoma.

Figure 1

Stimulatory and Inhibitory coreceptors regulate T-cell responses to tumor antigens. Notes: Tumor antigen recognition by T-cells is dependent on T-cell receptor (TCR) recognition of a peptide ligand major histocompatibility complex (MHC). Following TCR engagement, T-cell activation and acquisition of effector functions requires costimulatory signals mediated by CD28 binding to a B7 family molecule (B7.1 or B7.2) on the antigen-presenting cell (APC). Activation-induced upregulation of inhibitory receptors, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and others then acts to downmodulate T-cell effector functions when engaged with cognate ligands. CTLA-4 competes with CD28 for binding to B7 molecules expressed on APCs, an interaction occurring during T-cell priming in lymphoid tissues. PD-1 binds to its ligands PD-L1 or PD-L2. PD-L1 expression is upregulated on tumor cells by interferons or other stimuli within the tumor microenvironment that may allow tumor cells to evade an endogenous immune response. Antibody blockade or PD-1 or PD-L1 may augment the activity of T-cells specific for tumor antigens. From The New England Journal of Medicine, Ribas A, Tumor Immunotherapy Directed at PD-1, 366, Page No 2518. Copyright © (2012) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 2

Programmed cell death-ligand 1 (PD-L1; or B7-H1) expression on clear cell renal cell carcinoma tumor is associated with cancer-specific death. Notes: The expression of PD-L1 (B7-H1) detected on formalin-fixed paraffin-embedded tumor samples by immunostaining with the 5H1 antibody was analyzed on 306 clear cell tumors. Positive PD-L1 expression (≥5% of tumor cells) was seen in 24% of tumors. The risk ratio for cancer-specific death in patients with PD-L1⁺ tumors was 3.92 (95% confidence interval 2.61–5.88; P<0.001). Adapted from Cancer Research, Copyright 2006, 66(7), 3381–3385, Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is Associated with Poor Prognosis in Renal Cell Carcinoma Patients with Long-term Follow-up, with permission from AACR.