Dose– and time-dependent systemic immune modulation by stereotactic radiotherapy in early-stage lung cancer

Abstract Importance:There is an unmet need to understand the immunomodulatory mechanisms of stereotactic body radiotherapy (SBRT) to effectively enhance responses to immunotherapy, while reducing tumor burden.Objective:To evaluate the impact of ablative SBRT on systemic immunity in patients with early-stage NSCLC.Design:The LAPIS trial accrued patients between 2016-2021, with a median follow-up of 31 months. This primary analysis was based on data that were current as of December 14, 2021.Setting:Single center prospective clinical trial.Participants:Fifty-six patients with early-stage inoperable NSCLC patients treated with SBRT in different dose/schedules were enrolled, of whom 50 were evaluable.Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): We used immune profiling of peripheral blood at first SBRT fraction (baseline), during and at the end of SBRT as well as at first (FU1) and second (FU2) follow-up (six weeks and another 4.5 months after the last SBRT fraction, respectively).Main Outcome(s) and Measure(s): The pre-specified primary endpoint was increase (yes/no) in circulating CD8+ CTL counts at FU1 compared to pre-treatment, and secondary endpoints included changes in other T-cell subsets at all time-points.Results: Fifty patients with early-stage NSCLC (median age 70 years, male 68%, female 32%) were evaluated. The absolute counts of circulating CD8+ CTLs at FU1 increased only in 21% of the patients (not significant), but there was a statistically significant increase in the proportion of proliferating CD4+ and CD8+ T-cells immediately after SBRT (at the end of the treatment, p £ 0.01), also in the subsets expressing PD-1, containing tumor-specific T-cells (p £ 0.001). These effects were significant only in the subset of patients receiving 10Gy or less per SBRT fraction (n=25, p £ 0.05). At 2 and 4 years, OS rate was 75% and 51%, respectively, and progression-free survival (PFS) was 56% and 25%, respectively. A longer PFS was associated with an absolute increase of the CD8+ CTLs at FU1 compared to pre-treatment values (p=.04).Conclusions and Relevance: SBRT induces a significant expansion in subsets of circulating effector T-cells immediately post-treatment and support the testing of lower doses per fraction for SBRT prior to or combined with immunotherapy.Trial Registration: The study was registered accordingly in the German trials registry (DRKS 00011266).https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011266