Th136 - Patient-derived Lung Cancer Organoids as 3D-testing Platform for Advanced Personalized Therapies

Lukas Ehlen – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT). Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Berlin Institute of Health, Department of Anesthesiology and Intensive Care Medicine; Martin Szyska – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Janine Arndt – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Katerina Thiede – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Cedric Scholz – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Laura Golusda – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Rebecca Friederich – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Marco Mai – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Sarah Schulenberg – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Lena Peter – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Samira Picht – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Anna Löwa – Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Berlin Institute of Health, Department of Infectious Diseases and Respiratory Medicine; Regina Stark – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT); Claudia Vollbrecht – Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Berlin Institute of Health, Institute of Pathology; Maria Joosten – Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Berlin Institute of Health, Institute of Pathology; Andreas Hocke – Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Berlin Institute of Health, Department of Infectious Diseases and Respiratory Medicine; Simon Schallenberg – Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Berlin Institute of Health, Institute of Pathology; Claudia Spies – Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Berlin Institute of Health, Department of Anesthesiology and Intensive Care Medicine; Michael Schmueck-Henneresse – Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT)

Abstract Text: Lung cancer stands as the leading cause of global cancer-related deaths, prompting a critical need for new treatment options. While chemotherapy and radiotherapy are standard treatments for certain lung cancers, their efficacy is not sustained. Targeted antibodies and immune-checkpoint inhibitors (ICI), effective in a small subset of patients, encounter challenges due to high tumor heterogeneity. Adoptive cell therapy which involves the infusion of natural tumor-reactive T cells or genetically modified T cells to express chimeric antigen receptor (CAR), represents a promising alternative. To address tumor resistance mechanisms and personalize new therapies, models reflecting individual tumors are crucial.

We successfully established patient-derived lung tumor organoids and matched healthy organoids from surgically resected patient tissue. These organoids closely resemble the original tissue, validated through histology, DNA sequencing, and single-cell RNA sequencing. Acting as patient avatars, we systematically tested each patient's treatment regimen with our organoid platform ex vivo. Furthermore, proteomics analysis showed potential to identify therapy resistance mechanisms.

To develop alternative therapy options, we screened each patient organoid line for lung tumor-associated antigens (TAAs). As a proof of concept, we identified suitable TAAs for specific T-cell targeting, employing and generating corresponding CAR-T cells. These CAR-T cells demonstrated specific tumor organoid killing compared to healthy controls, indicating their potential as a therapeutic alternative. Our study establishes patient-derived organoids as avatars, utilizing a diverse set of immunotherapeutic approaches to inform and personalize therapy for lung cancer patients.