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

Abstract

Despite a proportion of renal cancer patients can experiment marked and durable responses to immunecheckpoint inhibitors, the treatment efficacy is widely variable and identifying the patient who will benefit from immunotherapy remains an issue. We performed a prospective study to investigate if soluble forms of the immune-checkpoints PD-1 (sPD-1), PD-L1 (sPD-L1), pan-BTN3As, BTN3A1, and BTN2A1, could be candidate to predict the response to immune-checkpoint blockade therapy. We evaluated the plasma levels in a learning cohort of metastatic clear cell renal carcinoma (mccRCC) patients treated with the anti-PD-1 agent nivolumab by ad hoc developed ELISA's. Using specific cutoffs determined through ROC curves, we showed that high baseline levels of sPD-1 (>2.11 ng/ml), sPD-L1 (>0.66 ng/ml), and sBTN3A1 (>6.84 ng/ml) were associated with a longer progression-free survival (PFS) to nivolumab treatment [median PFS, levels above thresholds: sPD-1, 20.7 months (p < .0001); sPD-L1, 19 months (p < .0001); sBTN3A1, 17.5 months (p = .002)]. High sPD-1 and sBTN3A1 levels were also associated with best overall response by RECIST and objective response of >20%. The results were confirmed in a validation cohort of 20 mccRCC patients. The analysis of plasma dynamic changes after nivolumab showed a statistically significant decrease of sPD-1 after 2 cycles (Day 28) in the long-responder patients. Our study revealed that the plasma levels of sPD-1, sPD-L1, and sBTN3A1 can predict response to nivolumab, discriminating responders from non-responders already at therapy baseline, with the advantages of non-invasive sample collection and real-time monitoring that allow to evaluate the dynamic changes during cancer evolution and treatment.

A “Lymphocyte MicroRNA Signature” as Predictive Biomarker of Immunotherapy Response and Plasma PD-1/PD-L1 Expression Levels in Patients with Metastatic Renal Cell Carcinoma: Pointing towards Epigenetic Reprogramming

“…It has also been observed that miR-200 expression negatively correlates with PD-L1 expression, suggesting the potentiality of miRNA expression as a predictive biomarker for immunotherapy response [ 44 ]. Previous studies showed that baseline levels of soluble PD-1 and PD-L1 were associated with a longer PFS to nivolumab treatment in a cohort of metastatic ccRCC patients, and high sPD-1 were also associated with best overall response by RECIST and objective response of >20% [ 45 , 46 , 47 ]. In our patient cohort, the inverse correlation between miR-22 and miR-24 levels and plasma PD-1 levels in long-responder patients suggests that a miRNA network could inhibit the immune checkpoint expression, mainly via the miR-20 family.…”

“…The plasma sPD-1 and sPD-L1 levels have been previously measured using specific homemade ELISA assays not yet commercially available, designed according to the investigator specifications, as previously described [ 47 , 56 , 57 ].…”

Prognostic Role of Plasma PD-1, PD-L1, pan-BTN3As and BTN3A1 in Patients Affected by Metastatic Gastrointestinal Stromal Tumors: Can Immune Checkpoints Act as a Sentinel for Short-Term Survival?

“…[50] in the following way: progression disease (PD), stable disease (SD), partial response (PR), complete response (CR). The peripheral blood specimens from untreated GIST patients (baseline) were processed for plasma isolation and subsequently stored as previously described [16,22].…”

Soluble BTN2A1 Is a Potential Prognosis Biomarker in Pre-Treated Advanced Renal Cell Carcinoma

“…In the previous NIVOREN GETUG-AFU 26 study, it was reported that tissue PD-1 and AXL expression by immunohistochemistry were associated with PFS and confirmed that PBRM-1 loss was a strong prognostic factor (10). Incorvaia et al explored the prognostic value of soluble forms of PD-1, PD-L1, global BTN3, BTN3A1 and BTN2A1 in a prospective cohort of metastatic renal cell carcinoma patients (11). They identified sPD-1, sPD-L1 and sBTN3A1 as potential biomarkers.…”