Dynamics of peripheral blood NKT cells and PD-L1-expressing classical monocytes as immune correlates of radiotherapy-primed atezolizumab in relapsed small cell lung cancer: a phase II study

We conducted a prospective phase II trial evaluating sequential hypofractionated radiotherapy followed by atezolizumab in relapsed small cell lung cancer (SCLC), with objective response rate (ORR) as the primary endpoint and peripheral blood immune profiling as a pre-specified exploratory objective to identify immune correlates of clinical outcomes. Thirty patients with relapsed/refractory SCLC after platinum-based chemotherapy received 24 Gy hypofractionated radiotherapy (4 fractions every other day) followed by atezolizumab (1200 mg every 3 weeks). Serial peripheral blood mononuclear cells (PBMCs) were profiled by multiparametric flow cytometry before and after radiotherapy. Natural killer T (NKT) cells (CD3 + CD56 + ) and programmed death-ligand 1 (PD-L1)-expressing classical monocytes (CD14 high CD16 − ) were assessed as immune correlates of progression-free survival (PFS). ORR was 80.0% for radiotherapy and 16.7% for atezolizumab. Median PFS was 2.5 months (6 month PFS: 6.9%) and median overall survival (OS) was 10.4 months (12 month OS: 41.8%). Patients with PFS ≥ 3 months showed lower baseline NKT frequency ( p = 0.02) and greater post-radiotherapy NKT expansion (fold-change 1.3 vs. 0.9; p = 0.011) than those with PFS < 3 months. Post-radiotherapy PD-L1 + classical monocyte fold-increase was greater in the longer-PFS group (2.8 vs. 0.7; p = 0.0085). Although systemic efficacy was modest in this unselected population, dynamic changes in circulating NKT cells and PD-L1-expressing classical monocytes emerged as distinct peripheral blood correlates of clinical benefit from radiotherapy-primed atezolizumab. These findings support further investigation of innate immune reprogramming as a biomarker strategy for patient selection in radio-immunotherapy combinations.