The utilization of patient-derived organoids as a platform for predicting the efficacy of anti-cancer drugs: Chemotherapy, targeted therapy, and immunotherapy.

Abstract

e15102 Background: Cancer is one of the leading causes of mortality worldwide. Current treatments are confronted with limitations, including drug resistance and relapse. To address these issues, the use of advanced in vitro models, such as patient-derived organoids (PDOs), is crucial. In contrast to conventional 2D cultures, PDOs closely resemble the biological characteristics of tumors. Therefore, PDOs serve as highly effective models for evaluating drug efficacy in vitro , predicting clinical drug responses and providing valuable insight into the development of new therapeutics. Methods: Over 800 PDOs were established from tissue or metastatic samples obtained from patients diagnosed with lung, colorectal, gastric, pancreatic, and ovarian cancer. Subsequently, mutations present in patients and their corresponding tumor organoids were analyzed using the GBCC DNA/RNA analysis pipeline. The variant allele frequency of each mutation was then calculated. The drug screening platform involved the treatment of organoids with drugs for a period of 5 days in 5% Matrigel, after which the cell viability was assessed using Cell Titer-Glo 3D. The immune cell co-culture platform involved the isolation of peripheral blood mononuclear cells and tumor-infiltrating lymphocytes from patient blood and tissue samples, followed by the evaluation of organoid viability and T-cell cytokine release by flow cytometry. Results: GBCC has developed two distinct organoid-based drug screening platforms to evaluate various cancer therapies. The initial drug screening platform employs organoids in isolation to evaluate the efficacy of anti-cancer drugs, encompassing chemotherapy and targeted therapy. This platform is capable of facilitating mono or combination drug screenings. It is noteworthy that lung PDOs harboring driver mutations, such as EGFR and KRAS, exhibited responsiveness to targeted therapeutic agents, with the outcomes corresponding to the treatment histories of the patients. Antibody-drug conjugates, including Trastuzumab Deruxtecan, demonstrated sensitivity in HER2-overexpressing gastric cancer organoids and lung cancer organoids with HER2 mutations. The second drug screening platform is a model that co-cultures organoids with autologous T cells to evaluate immune checkpoint inhibitors (ICIs). Co-culture platforms have shown that the viability of cancer organoids is significantly reduced in the presence of ICIs. Conclusions: Our organoid-based drug screening platforms can be utilized to assess drug responsiveness, providing a valuable tool for the preclinical drug evaluation, and supporting the advancement of precision medicine and the discovery of new cancer therapies.