Abstract A17: Ex vivo 3D functional drug response profiling using patient-derived cancer models: Clinical and regulatory considerations
Authors: DesRochers Tessa M. , Holmes Lillia , Gevaert Matt , Crosswell Hal E. 
Published: March 2017

Abstract
Introduction: Significant resources have been dedicated to the development of patient derived tumor models for precision medicine initiatives, including the NCI's Patient-Derived Models Repository. The majority of efforts are geared towards use of these patient derived in vitro models (3D cultures, organoids) in the pre-clinical drug discovery and development setting or use of patient-derived xenograft models in the co-clinical trial or clinical setting for determining patient-specific therapies. Our company is focused on developing patient-derived models for ex vivo 3D drug response profiling (EV3D) for real time clinical decision making. In this report, we highlight the development, drug testing and early validation efforts of clinically relevant 3D culture platforms amenable to multiple different types of solid tumors and classes of therapies for the purpose of predicting patient response.
Methods: With a goal of developing EV3D drug response profiling (DRP) tests to be used by treating physicians for predicting patient response, we focus our report on the intended late validation steps and regulatory considerations necessary for utilizing patient-derived in vitro models for precision medicine initiatives. Lead clinical programs include ovarian, breast, glioblastoma and lung cancer, with NCI-awarded contracts to support the development of more complex ex vivo models to be used for mimicking the tumor microenvironment's role in tumor heterogeneity, therapeutic resistance, and immune-protection. With a clinically impactful and regulated assay in mind, major considerations to be addressed include standardization of cell sources, 3D scaffolds and matrices, drugs and therapeutic application (including timing and combinations) and analytical assays. Methods of correlation of ex vivo drug response with molecular subtype, in vivo response and clinical response (biomarkers and outcomes) are addressed. Finally, considering that no functionally predictive in vitro cancer response assay has yet be fully validated to date, we describe future clinical trial plans aimed at validating our EV3D DRP platforms.
Conclusions: Patient-derived ex vivo 3D culture models have great promise for precision medicine initiatives, and our efforts highlight the benefits and barriers involved in developing and validating predictive in vitro 3D assays to be used in the clinic. Ultimately, multisite clinical trials will need to be performed to fully determine the clinical utility of patient-derived 3D models, and the regulatory and logistical aspects of this process must be considered early in the development phase of patient-derived tumor models for truly precision medicine applications.
Citation Format: Tessa M. DesRochers, Lillia Holmes, Matt Gevaert, Hal E. Crosswell. Ex vivo 3D functional drug response profiling using patient-derived cancer models: Clinical and regulatory considerations. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A17.