Building confidence in Liver MPS for regulatory decision making: The 3Rs Collaborative & FDA-CDER’s cross-platform DILI project​

The ability of microphysiological systems (MPS) to accurately predict human responses and subsequent implementation into different areas of drug development is being analysed worldwide. Increasing scrutiny is being implemented on the accuracy, robustness and reliability of different technologies, moving beyond proof-of-concept models to internal and regulatory decision-making tools. Regulators such as the FDA are implementing pathways to evaluate these methods against specific contexts of use (CoUs) to gain confidence in the tools. Recently, a letter of intent (LOI) was accepted to the FDA’s iSTAND programme for a cross-platform project to evaluate the ability of eight commercial liver MPS to detect drug-induced liver injury (DILI) by a consortium begun by the 3Rs Collaborative and FDA CDER. To qualify and compare each model, eight blinded compounds (4 hepatotoxic, 4 non-hepatotoxic paired controls) were provided to each company to test in parallel. Here, we present the results from one of the Liver MPS from this evaluation, where the compounds were tested on microtissues formed on a continuously perfused scaffold from primary human hepatocytes and Kupffer cells. Dosing occurred for 10 days in a 6- dose concentration range (0.05x to 10x Cmax). Markers for liver viability (LDH, ALT, AST) and functionality (albumin, bile acid, IL-6) were evaluated alongside CYP3A4 activity across the dosing period. All raw data was delivered to the NIH-NIEHS for independent analysis alongside results from other liver MPS. The study identified 4 hepatotoxic and 4 non-hepatotoxic compounds. A range of risk profiles and mechanisms of toxicity were identified. With the example of Drug 150, higher functional activity (increased albumin and CYP3A4) was detected up to 1x Cmax over the 10 days of dosing, after which toxicity was captured at 5x and 10x Cmax through increased LDH, ALT and AST and decreased albumin, IL6 and CYP3A4. Through the standardized evaluation of the eight liver MPS in the project, further confidence in the range of each MPS to detect DILI will be delivered, whilst giving a framework for future evaluation and standardization projects of MPS tools for drug development and regulatory acceptance.​

Development of a Perfused Melanoma MPS Incorporating a Transwell®‑Based Endothelial Monolayer to Evaluate Efficacy of a CAR T‑Cell Therapy

Preclinical models like microphysiological systems (MPS) are at the forefront of cancer research. However, models capturing the full immunological cascade of immunotherapeutic agents, such as CAR T cells, from circulation in the bloodstream through vascular transendothelial migration and infiltration into primary tumours, remain scarce. Recreating the physical and biochemical barriers imposed by the tumour microenvironment using advanced in vitro systems is critical for investigating CAR T‑cell performance against primary neoplasms, while simultaneously providing insights into potential adverse effects.

As part of Melomanes, an EU-wide research consortium dedicated to the development of an immunotherapy combining anti-HLA.CAR+T-cells and magnetic nanoparticles capable of inducing localised hyperthermia, this project aims to develop an advanced Melanoma-on-a-chip MPS model to evaluate therapeutic efficacy and safety of CAR T-cells.

This model was developed using the PhysioMimix® Core platform, under medium circulation to model blood flow. A Transwell®-based dual-compartment strategy enabled chemokine-driven immune cell migration across a HUVEC layer enabling subsequent investigation of immune cell activity against malignant tissue in a controlled microphysiological environment.

Such human-based preclinical models offer a roadway to predictive success whilst reducing the reliance on in vivo models.