Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy

Abstract

Modulating immune inhibitory pathways has been a major recent breakthrough in cancer treatment. Checkpoint blockade antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programed cell-death protein 1 (PD-1) have demonstrated acceptable toxicity, promising clinical responses, durable disease control, and improved survival in some patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other tumor types. About 20 % of advanced NSCLC patients and 30 % of advanced melanoma patients experience tumor responses from checkpoint blockade monotherapy, with better clinical responses seen with the combination of anti-PD-1 and anti-CTLA-4 antibodies. Given the power of these new therapies, it is important to understand the complex and dynamic nature of host immune responses and the regulation of additional molecules in the tumor microenvironment and normal organs in response to the checkpoint blockade therapies. In this era of precision oncology, there remains a largely unmet need to identify the patients who are most likely to benefit from immunotherapy, to optimize the monitoring assays for tumor-specific immune responses, to develop strategies to improve clinical efficacy, and to identify biomarkers so that immune-related adverse events can be avoided. At this time, PD-L1 immunohistochemistry (IHC) staining using 22C3 antibody is the only FDA-approved companion diagnostic for patients with NSCLC-treated pembrolizumab, but more are expected to come to market. We here summarize the current knowledge, clinical efficacy, potential immune biomarkers, and associated assays for immune checkpoint blockade therapies in advanced solid tumors.

Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

“…The currently approved IHC testing of biopsy tissue for PD-L1 expression is only a predictor of response in patients with very high levels of PD-L1 expression, yet many PD-L1-negative patients will also benefit (29,30,33,(39)(40)(41)(42)46). This discrepancy may be attributed to the dynamic nature of immune modulation expression and/or the inability to analyze the stromal cell components.…”

“…This discrepancy may be attributed to the dynamic nature of immune modulation expression and/or the inability to analyze the stromal cell components. Because immune checkpoint protein expression is dynamic, being influenced by multiple microenvironmental, inflammatory, and therapy factors, it has been hypothesized that blood-based analysis may provide a more accurate representation of the current PD-L1 expression in patients (29,30,39,42,43,47,48). Interestingly, we found three classes of PD-L1 responses in the circulating cells of patients, those that are persistently low, persistently high, or inducible from low to high, which occurs in about one-third of patients (32%).…”

“…In tissue biopsies, expression of the biomarker PD-L1 alone is not a prognostic indicator of survival in lung cancer, while RAD50 foci formation has been indicated as positively correlated with survival (14,18,20,24,29,30,32,35,39,40,42). We analyzed the clinical outcomes of patients based on expression of PD-L1, or the average number of RAD50, at both T0 and T1 time points (Fig.…”

“…PD-L1/PD-1 immune blockade drugs (e.g., nivolumab and pembrolizumab) are potent immune checkpoint inhibitors that have been shown to dramatically shrink and stabilize tumors in approximately 20% of patients with NSCLCs (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). These types of immunotargeted therapeutics specifically alter a patient's stromal interactions by activating the host's immune cell response against the presence of tumor cells (29-36, 41, 42).…”

PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells

“…8 Furthermore, recently introduced CTLA4, PD-1 and PD-L1 immune checkpoint inhibitors have had no 9 or only moderate effects on NSCLC. [10][11][12][13] Therefore, novel treatment regimens are still needed.…”