Effect of exogenous interferon-gamma (IFN-gamma) on peripheral blood immune markers as part of a phase I clinical trial of combined IFN-gamma with nivolumab (Nivo) in patients (pts) with select solid tumors.

Abstract

97 Background: IFN-gamma is a known activator of PD-L1 expression and plays a key role in immune activation. We present initial correlative peripheral blood findings after the first 2 cohorts of pts enrolled in a phase I trial of combined IFN-gamma/Nivo in pts with various solid tumors. Methods: Pts with advanced solid tumors who had progressed after at least 1 prior therapy were recruited. An induction phase of IFN-gamma (50 or 75 mcg/m2 subq every other day for 1 week) preceded the combination of Nivo (3 mg/kg IV every 2 weeks) with continuation of IFN-gamma at same dose and schedule for 3 months. Pts with clinical benefit could remain on Nivo alone for up to 1 year. Peripheral blood was analyzed via flow cytometry at baseline, after IFN-gamma induction (prior to Nivo start), and after 6 weeks of combo treatment. Results: 13 pts have been accrued. Pre and post induction samples were collected on all pts. Nine pts had available on-treatment samples at time of data analysis. Comparing blood collections from baseline to post-IFN-gamma induction revealed a substantial expansion of the CD14high, CD16+ monocyte population (p=0.001) and a statistically significant increase in MHC class II expression on all monocyte populations (p≤ 0.002 for all types). Natural killer (NK) cells demonstrated greater numbers of cells per ml of blood (p=0.03) and increased NKp30 expression, an important receptor mediating tumor cell lysis (p= 0.005 for CD56dim; p= 0.03 for CD56bright). With the addition of Nivo, evidence for activation of CD56dim NK cells was detected as increased CD69 expression compared to post-induction (p=0.02). PD-1 expression on T-cells showed reduced expression in most comparators after initiation of Nivo (p=0.055 CD8+; p=0.008 CD4+). Conclusions: Early correlative peripheral blood data demonstrate expected systemic IFN-gamma effect as measured by monocyte activation and increased MHC II expression. Evidence of NK cell activation and proliferation was also observed. Decreased PD-1 expression on T-cells may reflect down-regulation in response to PD-1 blockade. Correlations with biopsy specimens and clinical response are planned. Clinical trial information: NCT02614456.