Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab

Abstract

Controversial results on the predictive value of programmed death ligand 1 (PD-L1) status in lung tumor tissue for response to immune checkpoint inhibitors do not allow for any conclusive consideration. Liquid biopsy might allow real-time sampling of patients for PD-L1 through the course of the disease. Twenty-four stage IV NSCLC patients included in the Expanded Access Program with Nivolumab were enrolled. Circulating tumor cells (CTCs) were analyzed by CellSearch with anti-human B7-H1/PD-L1 PE-conjugated antibody. PD-L1 expressing CTCs were assessed at baseline, at 3 and 6 months after starting therapy, and correlated with outcome. At baseline and at 3 months of treatment, the presence of CTCs and the expression of PD-L1 on their surface were found associated to poor patients outcome. Nevertheless, the high frequency of PD-L1 expressing CTCs hampered to discriminate the role of PD-L1 in defining prognosis. Conversely although CTCs were found in all patients 6 months after treatment, at this time patients could be dichotomized into two groups based PD-L1 expression on CTCs. Patients with PD-L1 negative CTCs all obtained a clinical benefit, while patients with PD-L1 (+) CTCs all experienced progressive disease. This suggests that the persistence of PD-L1(+) CTCs might mirror a mechanism of therapy escape.

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

“…Although there is discordance in the literature regarding expression and prognostic value of PD-L1 in CTCs, our results are more in line with our understanding of PD-L1 expression and prognostic significance in tumor biopsies (24,(47)(48)(49). Initial research on PD-L1 in CTCs has given conflicting results based on our understanding of the PD-L1 cascade.…”

“…These conclusions are in contrast with general IHC testing of primary tumor masses, which finds little to no correlation between PD-L1 expression in biopsies and survival, when PD-L1/PD-1 therapeutics are not used (29-31, 36-41, 46). Furthermore, only a small fraction of patients will actually respond to PD-L1/PD-1 therapy, indicating that the reported CTC assays may be overly sensitive for detecting PD-L1 and will unlikely translate to clinical benefit for PD-L1/PD-1 therapies (16,(47)(48)(49)). An alternative issue may be that many CTC technologies do not differentiate the EMTCTC subpopulation from the CellSearch CTC population (i.e., PDCTCs), or make any mention of CStCs (3,4,6,7,16,17,(47)(48)(49).…”

“…Furthermore, only a small fraction of patients will actually respond to PD-L1/PD-1 therapy, indicating that the reported CTC assays may be overly sensitive for detecting PD-L1 and will unlikely translate to clinical benefit for PD-L1/PD-1 therapies (16,(47)(48)(49)). An alternative issue may be that many CTC technologies do not differentiate the EMTCTC subpopulation from the CellSearch CTC population (i.e., PDCTCs), or make any mention of CStCs (3,4,6,7,16,17,(47)(48)(49). These methods describe a BBB approach that differentiates CAMLs and the PDCTC/EMTCTC subpopulations by well-defined intrinsic biological indicators, that is, EMTCTCs lose EpCAM and downregulate cytokeratin (6,10,11,13,14,43).…”

Challenges and unanswered questions for the next decade of circulating tumour cell research in lung cancer

“…More recently, expression of PDL-1 in CTCs has been examined in trials with immune checkpoint inhibitors and has linked with patients who experienced progressive disease (177).…”

Biology and clinical significance of circulating tumor cell subpopulations in lung cancer

“…In a recent study Nicolazzo et al investigated PD-L1 expression on CTCs in 24 patients receiving nivolumab (61). Despite showing a significance between PD-L1 positivity and poor outcome in late stage treatment (6 months) of NSCLC patients, the authors highlighted a lack of distinction between PD-L1 positivity and outcome at baseline and early treatment (3 months) in this small patient cohort (61 The role of nuclear PD-L1 (nPD-L1) expression was also reported in vimentin positive CTCs of metastatic colorectal and prostate cancer patients (64).…”