IMMUNOMODULATION INDUCED BY ENDOSCOPIC ULTRASOUND-GUIDED ABLATION WITH THE HYBRIDTHERM PROBE IN STAGE III PANCREATIC DUCTAL ADENOCARCINOMA: SINGLE-CENTER PRELIMINARY RESULTS FROM A PHASE II/III RANDOMIZED-CONTROLLED TRIAL

Background &Aim: Endoscopic Ultrasound-guided ablation with the HybridTherm Probe (EUS-HTP) in patients (pts) with locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) showed to induce significant tumor volume reduction at 1-month follow-up, positive correlation between survival and necrotic volume/lesion volume ratio, and better survival in pts unfit for chemotherapy (CHT) after failure of 1st-line therapy. In this study we aimed to investigate the immunomodulatory effect of EUS-HTP, comparing with the one induced by CHT. Methods: Pts with LA and borderline resectable (BR) PDAC without underlying immune-mediated disorders nor concomitant tumors were randomized to EUS-HTP plus CHT arm (HTP+CHT) or CHT alone arm (randomized controlled trial NCT02336672). HTP (ERBE), combining bipolar radiofrequency ablation with cryogenic CO2 cooling effect, was used under EUS-guidance. Up to 3 EUS-HTP sessions were performed, 1-month apart. Peripheral blood mononuclear cells were obtained before treatment, at 2- and 4-month follow-up. The following T-cell subsets were evaluated by flow-cytometry: CD4+ T-helper cells (Th1,Th2,Th17), T-follicular helper cells (Tfh1,Tfh2,Tfh17), CD4+ and CD8+ T-cytotoxic lymphocytes (CTLs), T-regulatory cells (Tregs). Age-/ sex-matched healthy donors (HDs) served as controls. Results: In this preliminary analysis, we enrolled 5 pts treated with HTP+CHT (M/FZ2/3, 70.6 6.3 years, LA/ BRZ4/1), 5 pts treated with CHT (M/FZ3/2, 65.4 5.4 years, LA/BRZ4/1) and 10 HDs (M/FZ4/6; 65 7.9 years). Pts underwent Nab-Paclitaxel+Gemcitabine or Fol firinox, without differences between the 2 groups. At baseline, PDAC pts presented higher levels of Th cells, T-effector memory cells (TEMs), Tfh cells, Treg cells, and CD4+ CTLs compared to HDs, although the difference was not statistically signifi cant. Assessing the levels of the different T-cell subsets over time, no statistically significant difference was observed both intra-patient and inter-patient at 2- and 4- month follow-up. However, some trends compared to baseline were observed, such as stability up to 4-month of Treg cells in HTP+CHT pts whereas increased in CHT pts, and stability up to 4-month of CD4+ CTLs and TEM cells in HTP+CHT pts whereas decreased in CHT pts. Conclusions: This study is the first assessing the EUS HTP immunomodulation effect in pts with stage III PDAC. Although a certain degree of T-cell immunomodulation was observed in HTP+CHT pts, this was not significant. These preliminary results are biased by the small number of pts and combi nation of EUS-HTP with CHT that might have masked some immunomodulatory effects specific to HTP. We cannot exclude that more relevant changes in the im mune response occur at tissue level and are not evident in the peripheral blood. Further analyses on other immune cells and plasma cytokines are ongoing to correlate these results with clinical outcome