Increased Plasma Soluble PD-1 Concentration Correlates with Disease Progression in Patients with Cancer Treated with Anti-PD-1 Antibodies

Abstract

Immune checkpoint inhibitors (ICIs) confer remarkable therapeutic benefits to patients with various cancers. However, many patients are non-responders or develop resistance following an initial response to ICIs. There are no reliable biomarkers to predict the therapeutic effect of ICIs. Therefore, this study investigated the clinical implications of plasma levels of soluble anti-programmed death-1 (sPD-1) in patients with cancer treated with ICIs. In total, 22 patients (13 with non-small-cell lung carcinoma, 8 with gastric cancer, and 1 with bladder cancer) were evaluated for sPD-1 concentration using enzyme-linked immunosorbent assays for diagnostic and anti-PD-1 antibody analyses. sPD-1 levels were low before the administration of anti-PD-1 antibodies. After two and four cycles of anti-PD-1 antibody therapy, sPD-1 levels significantly increased compared with pretreatment levels (p = 0.0348 vs. 0.0232). We observed an increased rate of change in plasma sPD-1 concentrations after two and four cycles of anti-PD-1 antibody therapy that significantly correlated with tumor size progression (p = 0.024). sPD-1 may be involved in resistance to anti-PD-1 antibody therapy, suggesting that changes in sPD-1 levels can identify primary ICI non-responders early in treatment. Detailed analysis of each cancer type revealed the potential of sPD-1 as a predictive biomarker of response to ICI treatment in patients with cancer.

Establishment of a Monoclonal Antibody-Based Enzyme-Linked Immunosorbent Assay to Measure Soluble B7-H5 in Patients with Cancer

“…Recent evidence indicated that soluble B7-CD28 family inhibitory immune checkpoint molecules have been correlated with the progression of cancer and immunotherapy [ 15 ]. For example, the concentration of plasma soluble PD-1 was significantly increased in non-small-cell lung carcinoma, GC, and bladder cancer patients treated with anti-PD-1 antibody and correlated with tumor size progression [ 16 ]. The levels of serum soluble B7-H3 were upregulated in patients with GC and were positively associated with TNM stage or with infiltration depth T3/T4 or with lymph node metastasis [ 22 ].…”

“…Recently, soluble forms of immune checkpoint molecules including PD-1, PD-L1, B7-H3, and B7-H4 in cancer have been demonstrated to be correlated with advanced stage, metastatic status, prognosis, and ICI treatment of patients with cancer [ 15 , 16 ]. Similar to most immune checkpoint molecules, B7-H5 also has a soluble form and contributes to various diseases [ 17 , 18 ].…”

Emerging Immune-Monitoring System for Immune Checkpoint Inhibitors

“…In patients with NSCLC and gastric cancer, significance was found to correlate with decreased soluble PD-L1 levels and tumor regression after four cycles of PD-1 Ab [ 41 ]. Changes in plasma soluble PD-1 concentrations before and after two and four cycles of anti-PD-1 antibody treatment were significantly correlated with tumor size progression [ 42 ]. PD-L1 + CD14 + monocytes in peripheral blood are correlated with shorter survival in patients treated with anti-PD-1 antibodies, including NSCLC, gastric cancer, melanoma, parotid cancer, and bladder cancer [ 43 ].…”

Harnessing Liquid Biopsies to Guide Immune Checkpoint Inhibitor Therapy

“…Pretherapeutic higher sPD-1 plasma levels have shown to predict advanced disease state and to a lesser extent a worse prognosis. Any increase in sPD-1 plasma level post therapeutically have been correlated with improved survival for various cancers [ 27 , 120 ]. Multiple analysis demonstrates serum PD-1/PD-L1 as an independent predictor of survival upon anti-PD-1 therapy [ 120 ].…”

“…Any increase in sPD-1 plasma level post therapeutically have been correlated with improved survival for various cancers [ 27 , 120 ]. Multiple analysis demonstrates serum PD-1/PD-L1 as an independent predictor of survival upon anti-PD-1 therapy [ 120 ]. Serum PD-1 and PD-L1 has the potential to select patients for PD-1-based therapy, however, the reported levels of PD-L1 and PD-1 can be highly variable, due to differences in techniques used to quantify them and their associated limitations.…”