OPTIMAL METHODS TO CHARACTERIZE ADC RESISTANCE IN SOLID TUMORS AND IDENTIFY CLINICALLY USEFUL BIOMARKERS

Over the past 5-years, antibody drug conjugates (ADCs) have shown impressive improvements in survival outcomes of solid tumors and hematological malignancies.

With 14 ADCs already approved across different countries and more than 140 that entered the clinical development, they are intended to replace standard chemotherapies across multiple tumor types over the next decade.

Although ADCs show great clinical efficacy, resistance eventually occurs, and it becomes critical to understand resistance mechanisms to guide the choice of the following lines of therapy for patients who progress on a given ADC.

Given the complex nature of ADCs, immunocompromised mouse models (nude mice, NOD-SCID or NOG mice) and currently used clinical assays (standard radiology, IHC, WES etc) are not the optimal preclinical and clinical tools, to identify the multiple causes of resistance.

The OASIS project aims to generate a biobank of different patient-derived organoids (PDOs), which better recapitulate ADCs resistance and integrate different assays, spanning from whole-body molecular imaging (Ab-radiolabeled PET scan or immunoPET), circulating tumor cells (CTC), plasma proteomics, to multiplex immunofluorescence (MIF) and machine-learning enhanced digital pathology (AI-digital pathology) to capture most of the parallel mechanisms of resistance to ADCs.

Such tools will enable to define biomarkers of ADC resistance that can inform further therapeutic decisions.