Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT) Berlin, Berlin, Germany
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.
