Tumor immune dynamics and long-term clinical outcome of stage IIIA NSCLC patients treated with neoadjuvant chemoimmunotherapy
Dominic Schmid, Bettina Sobottka, Massimiliano Manzo, Marta Trüb, Katharina Leonards, Petra Herzig, Oluwaseun Rume-Abiola Oyewole, Philip Jermann, Stefanie Hayoz, Spasenija Savic Prince, Giulia Tochtermann, Marina Natoli, Miklos Pless, Adrienne Bettini, Martin Früh, Laetitia Mauti, Christian Britschgi, Solange Peters, Michael Mark, Adrian F. Ochsenbein, Wolf-Dieter Janthur, Christine Waibel, Nicolas Mach, Patrizia Froesch, Martin Buess, Pierre Bohanes, Michel González, Ilaria Alborelli, Sacha I. Rothschild, Viktor H. Koelzer, Alfred Zippelius
Abstract
Neoadjuvant chemoimmunotherapy offers promise to improve outcomes for patients with resectable non-small cell lung cancer (NSCLC). Yet not all patients derive treatment benefits, and reliable biomarkers of response are still lacking. We here assess the long-term clinical outcome of neoadjuvant chemotherapy and perioperative anti-PD-L1 inhibition in resectable stage IIIA NSCLC in the SAKK 16/14 trial and provide a comprehensive characterization of anti-tumor immune responses for biomarker-based treatment personalization. We report secondary outcomes of median event-free survival (EFS) of 4.0 years and median overall survival not being reached after a median follow-up of 5.4 years. Computer-aided spatial image analysis emphasizes the importance of CD8+ T cell positioning in tumors, and larger tertiary lymphoid structures in pre-treatment biopsies correlate with improved EFS. Genomic techniques reveal the association of intratumoral TCR diversity with response. Finally, circulating proliferating CD39+ PD-1+ CD8+ T cells and elevated levels of CCL15 post-treatment are seen in patients with sustained therapeutic benefit. NCT02572843. Neoadjuvant immunochemotherapy against NSCLC has been tested in clinical trials. Here, the authors follow up longer-term survival and measure immune cell phenotype changes in a single-arm phase II clinical trial of neoadjuvant immunochemotherapy, indicating association of intratumoural TCR diversity and CD8 T cell positioning.