210P - Precision immuno-oncology strategies to overcome drug resistance in non-small cell lung cancer

Background

Lung cancer is a major public health issue and the leading cause of cancer-related mortality. Despite recent advances in non-small cell lung cancer (NSCLC) treatment, drug resistance and variable treatment responses remain significant challenges. These issues are driven by tumor heterogeneity and diverse immune responses, leading to treatment failure. Our research addresses these challenges by investigating intrinsic resistance mechanisms and developing precision tools to enhance therapeutic strategies.

Methods

We have established a living biobank of tumor organoids, patient-matched immune cells, and cancer-associated fibroblasts from >200 lung cancer patients at The Helsinki University Hospital. These patient-derived tissues allow us to create precision ex vivo models that replicate the patient’s own tumor (immune) microenvironment, enabling us to better study therapy efficacy & resistance.

Results

By using these models, we have identified a minor subpopulation of EGFR-mutant NSCLC cells with low EGFR expression, which showed resistance to EGFR inhibitors with an invasive phenotype. Furthermore, these cells secrete cytokines that promote a drug-tolerant immune microenvironment and suppress antitumor immunity. We discovered, that epigenetic modulators can be utilized to increase the mutant EGFR expression and restore treatment sensitivity, suggesting a novel combination therapy strategy (Nature Com., in press). Additionally, we developed an ex vivo platform to analyze patient-specific immune responses and predict personalized immunotherapy outcomes. We discovered a combination of anti-PD-1 therapy and a novel Cbl-b inhibitor that overcomes primary anti-PD-1 resistance in a subset of patients, with specific biomarkers predicting therapy success (Science Adv., in press).

Conclusions

Our findings underscore the potential of combining targeted and immunomodulatory therapies as well as using fully human models to discover and study the mechanisms of new treatments.

Legal entity responsible for the study

University of Helsinki.

Funding

Orion Pharma.

Disclosure

H.M. Haikala: Non-Financial Interests, Institutional, Funding, Additional research funding for the described study: Orion Pharma. S. Mustjoki: Financial Interests, Personal and Institutional, Funding: Novartis, Pfizer, BMS; Financial Interests, Personal, Funding: Dren-Bio. All other authors have declared no conflicts of interest.