190P - Ex vivo modeling of precision immuno-oncology responses in lung cancer

Background

Immunotherapy has changed the treatment landscape in some cancers and even led to favorable outcomes in previously incurable cancer types. Despite the potential benefits, only a fraction of patients respond to current immuno-oncology (IO) treatments. Lack of predictive biomarkers, unknown mechanisms of immune resistance, complex tumor-immune interactions, and the understudied role of the tumor microenvironment pose significant challenges to the use of IO drugs. Moreover, predicting which patients would benefit from the expensive new treatments remains a significant challenge.

Methods

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 the patient's immune cells with autologous tumor organoids. This is followed by a tumor-killing assay utilizing the stimulated immune cells with or without different immunotherapy combinations. Lastly, we single-cell sequence different treatment conditions to reveal changes In order to establish this the immune and tumor cells following their interactions.

Results

Single-cell sequencing revealed immune response mechanisms and sensitivities to standard of care immunotherapies. Furthermore, we were able to identify a synergistic combination of anti-PD-1 together with a Cbl-b inhibitor that overcame anti-PD-1 resistance in selected patient samples. Activation of the interferon gamma-stimulated cytokines predicted combination efficacy, while immunosuppressive cytokines were associated with poor response.

Conclusions

Our findings underscore the platform's potential in tailoring immunotherapies and advancing drug development, offering new avenues for personalized cancer treatment.

Legal entity responsible for the study

HaikaLab, Immuno-Oncology Research Group.

Funding

Orion Pharma.

Disclosure

E. Narvi, A. Thotakura: Financial Interests, Personal, Full or part-time Employment: Orion Pharama. S. Mustjoki: Financial Interests, Personal and Institutional, Principal Investigator, Honoraria and research funding (not related to this study): Novartis, Pfizer, Bristol Myers Squibb, Dren-Bio. All other authors have declared no conflicts of interest.