Abstract B018: <i>Ex vivo</i> modeling of precision immuno-oncology responses in lung cancer

Abstract Immunotherapy has transformed cancer treatment, offering promising outcomes even in previously incurable cancers. However, responses to immuno-oncology (IO) treatments remain limited, with only a fraction of patients benefiting from these therapies. This limited efficacy arises from a lack of predictive biomarkers, unknown mechanisms of immune resistance, and the complex tumor-immune interactions, making it challenging to predict which patients will benefit from these costly treatments. To address these issues, we developed a precision ex vivo platform that integrates patient-specific tumor and immune cells to study the mechanisms of antitumor immune response, predict immunotherapy outcomes, and identify effective treatments. In order to establish this, we first stimulate patient-derived immune cells with autologous tumor organoids, followed by a tumor-killing assay using the stimulated immune cells in the presence or absence of different IO combinations. Lastly, single-cell sequencing is performed across different treatment conditions to reveal changes in immune and tumor cells following their interactions. Our ex vivo model demonstrated the ability to mimic primary resistance to anti-PD-1 therapy in lung cancer, enabling the identification of individual responders to anti-PD-1 combination with chemotherapy agents. Additionally, we identified a synergistic IO-drug combination: anti-PD-1 with a Cbl-b inhibitor, which successfully overcame anti-PD-1 resistance in some patients. Moreover, interferon gamma-stimulated cytokines were predictive of combination efficacy, whereas the presence of immunosuppressive cytokines correlated with poor response. Finally, single-cell sequencing revealed immune response mechanisms and sensitivities to standard of care immunotherapies. Our findings underscore the platform's potential in tailoring immunotherapies and advancing drug development, offering new avenues for personalized cancer treatment. Citation Format: Bassel Alsaed, Johannes Smolander, Lin Linh, Nina Bobik, Hanna Laitinen, Lilja Lahtinen, Mikko Räsänen, Shadi Jansouz, Karita Peltonen, Emmi Jokinen, Jay Klievink, Mari Ainola, Eva Sutinen, Pipsa Saharinen, Satu Mustjoki, Ilkka Ilonen, Heidi Haikala. Ex vivo modeling of precision immuno-oncology responses in lung cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B018.