Lukas Ehlen, Martí Farrera-Sal, Martin Szyska, Janine Arndt, Simon Schallenberg, Cedric Scholz, Mingxing Yang, Claudia Vollbrecht, Anna Löwa, Rebecca Friedrich, Marco Mai, Lena Peter, Samira Picht, Sarah Schulenberg, Daniel Geray, Gabriela Korus, Anke Sommerfeld, Denise Treue, Julia Strauchmann, Aron Elsner, Jonas Kath, Valeria Fernandez Vallone, Maria Joosten, Franka Klatte‐Schulz, Ansgar Petersen, Harald Stachelscheid, Dimitrios L. Wagner, Claudia Spies, Jens‐Carsten Rückert, Andreas C. Hocke, Julia K. Polansky, Regina Stark, Oliver Klein, Michael Schmueck-Henneresse
Lung cancer, the leading cause of cancer-related mortality, presents major challenges for both standard therapies and chimeric antigen receptor (CAR) T cell therapy due to tumour heterogeneity and resistance. Preclinical models that capture patient-specific factors are essential for personalizing treatment decisions. Here we show that matched lung tumouroids and healthy lung organoids derived from patients provide a robust platform for studying therapy responses. The tumouroids faithfully retained the molecular and histological identity of the original tumours, as confirmed by genomic, epigenomic and proteomic analyses, and accurately replicated individual patient responses to standard-of-care therapies. Importantly, the platform also revealed patient-specific CAR T cell responses, uncovering a complex interplay between target antigen density and broader, tumour-intrinsic resistance programmes. By capturing these individualized factors, our model supports rational patient selection for CAR T cell therapy in lung cancer and provides a framework for designing CAR T cells tailored to overcome resistance mechanisms in solid tumours.