Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study

Abstract

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55–109) vs. 658 days (222-not reached); HR: 4.12 (1.95–8.71), p = 0.0002) and OS (HR: 3.99(1.63–9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17–6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30–0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21–0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.

Baseline plasma levels of soluble PD-1, PD-L1, and BTN3A1 predict response to nivolumab treatment in patients with metastatic renal cell carcinoma: a step toward a biomarker for therapeutic decisions

“…sPD-L1 concentrations were also correlated with the tumor burden, evaluated according to the number of metastatic sites, and the IMDC Prognostic Risk Groups While the role of sPD-1 is yet to be elucidated, the results related to sPD-L1 might be explained by the recent knowledges on soluble form of PD-L1 molecules, derived from an alternative splicing of PD-L1 mRNA or from a proteolytic cleavage of membrane-bound PD-L1, and proposed as a potential mechanism used by tumor cells to escape from T-lymphocytes-mediated immune surveillance. 41 The findings of higher sPD-L1 levels in the intermediaterisk subgroup than favorable, and in patients with non-lung metastases, confirms previous literature data on poorer outcome of bone or liver metastases than lung metastases 3 and highlights the potential prognostic impact of sPD-L1.…”

“…Previous studies proposed that the soluble form of PD-1 binds the PD-L1 on cancer cells membrane, preventing the interaction with its PD-1 natural ligand, thus limiting the coinhibitory signal on T lymphocytes and consequently enhancing antitumor response. 41 The biological reason why elevated plasma sPD-1 is associated with better response to nivolumab could be explained by these observations. Thus, patients with high levels of sPD-1 may benefit from synergic effect of proimmunologic sPD-1 and anti-PD-1 antibody nivolumab.…”

Emerging Blood-Based Biomarkers for Predicting Response to Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer

“…In the nivolumab group, baseline sCombo positivity was negatively related to PFS (HR = 2.66, p = 0.02) but not OS. Notably, increased or stable sPD-1 levels after two cycles of treatment with nivolumab was correlated with prolonged PFS (HR = 0.49, p = 0.004) and OS (HR = 0.39, p = 0.002) (95). In conclusion, sPD-L1 may represent a novel biomarker for guiding patient selection and predicting clinical outcomes.…”

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

“…This is due to the ability of sPD-1 to suppress all three combinations (PD-L1/PD-1; PD-L2/PD-1; PD-L1:B7-1) known to inhibit the immune response and also to the fact that sustained serum sPD-1 levels can still exert strong therapeutic effects while reducing the side effects that often occur with the use of anti-PD-1 mAbs [144]. In addition, considering that not all patients benefit from mAbs therapies, the identification of prognostic markers is becoming strictly required [145,146].…”