Ex Vivo Organ Culture for Rapid Tailoring of Patient-Specific Anti-Cancer Therapy

Introduction: Precision cancer therapy depends on correctly predicting each patient’s response to treatment according to the unique characteristics of their tumor. Genetic profiling can direct clinical decision making, however evaluation of the data is complex and in many cases has low predictive value. Alternative functional methods for tailoring patient-specific treatments include patient-derived cell lines, organoids and xenograft tumors (PDX). While attractive, these methods require a substantial investment of time and money, and cannot appraise the important impact of the human tumor microenvironment on drug response.

Recently, Ex-Vivo Organ Culture (EVOC) systems have also been utilized to predict response to anti-cancer drugs. The EVOC technology preserves the 3D structure, heterogeneity and complexity of the original tumor allowing rapid tailoring of patient-specific therapies. In this study we optimized this technology, tested its predictive value using PDX mouse models and used it to test the viability of 80 human tumors to demonstrate differential responses to anti-cancer therapy. Lastly, we treated selected patients according to the results in EVOC and tested the predicitive power of our system.

Materials and Methods: 250uM tumor sections are incubated in an oxygen chamber and treated with a large panel of drugs and drug combinations for up to 7 days. At the end of the experiment viability of each slice is assessed by pathological examination of standard H&E staining as well as by staining for multiple markers reporting on proliferation, cell death, and the flux in multiple cellular signaling pathways.

Results and Discussion: EVOC could correctly predict the response of seven PDX models to all tested drugs. No false positive or negative results were observed for these seven models. Eighty human tumors of various types were tested by EVOC. In 10 cases the tissue was found to be dead on arrival and in an additional 10, tumor cells were not present.. In 95% of the remaining 60 tumors we observed good viability at the end of the experiment thereby demonstrating the ability of our optimized conditions to keep EVOC slices of multiple human tumor types alive for up to seven days. For a cohort of 40 colorectal tumors we were able to demonstrate a wide range of responses for clinically relevant anti-cancer drugs. Lastly, in the few patients that were treated based on EVOC results, clear clinical responses were observed.

Conclusion: The EVOC system is a rapid, cost effective and accurate method of optimizing personalized anti-cancer therapy.