PD-1 blockade by anti-PD-1 antibodies restore the function of exhausted T cells and release perforin, granzyme B and cytokines which induce cytotoxic activity against tumor cells. We examined serum perforin, granzyme B and immune modulators as biomarkers of response to PD-1 blockade in non-small cell lung cancer (NSCLC) patients.
Advanced NSCLC patients treated with nivolumab or pembrolizumab were studied. Serum were collected on days 1, 2, 8 and 15 for nivolumab and on days 1, 2, 8, 15 and 22 for pembrolizumab. Concentration of perforin was determined by enzyme-linked immunosorbent assay (ELISA) and ten immune modulators, including granzyme B, were measured by a multiplex immunoassay. Best objective response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients were followed more than 3 months.
Plasma samples were obtained from 29 patients with nivolumab and 18 patients with pembrolizumab. With nivolumab, in 57% of responding patients, there were two aspects; (i) baseline levels of perforin concentration were higher in responders than in non-responders, or (ii) a ratio of perforin concentration on day 2 to the baseline was elevated (≧1.2). With pembrolizumab, there were no significant differences in baseline concentration between responders and non-responders. If patients who passed away within 3 months were excluded, in responding patients, a ratio of perforin concentration on day 22 to the baseline were significantly higher than in non-responders (partial response vs. progressive disease, p = 0.0330). The multiplex assay was performed on a part of samples (nivolumab, n = 10 and pembrolizumab, n = 6). By the multiplex assay, two out of 10 immune modulators were detected in more than 30% of samples; CD137 and FAS ligand. The correlation between these two analytes and the response to anti-PD-1 antibodies were hard to determine.
From serum, most immune modulators were difficult to measure. Sequential changes in perforin levels and the efficacy by two different anti-PD-1 antibodies were dissimilar. Concentration of serum perforin during the first cycle could be used to predict response to anti-PD1 antibody therapies in advanced NSCLC patients.
Clinical trial identification
Legal entity responsible for the study
The Osaka Medical Research Foundation for Intractable Diseases.
All authors have declared no conflicts of interest.