Animal testing has shaped modern drug development for decades, but its limitations become especially visible when scientists evaluate cancer immunotherapies. These treatments are designed to stimulate the immune system to recognize and destroy malignant cells, yet the same powerful immune activation can trigger life-threatening complications in patients. Researchers at the University of Rochester are developing a human-cell-based alternative: miniature tissue models known as organs-on-a-chip that could help predict these toxicities before experimental medicines reach clinical trials.
The work is being led through the university’s Translational Center for Barrier Microphysiological Systems, or TraCe-bMPS. The center is building drug-development tools around modular µSiM tissue chips, devices that contain ultrathin membranes populated with human cells. Unlike conventional laboratory cultures, these systems are engineered to reproduce key features of biological barriers, including the physical separation between tissues, controlled exposure to drugs, and measurable inflammatory responses. Their modular construction also allows the devices to be manufactured in large quantities with consistent dimensions and materials.
The platform is based primarily on acrylic components and incorporates membranes designed to mimic interfaces found in the human body. Such barriers regulate the movement of molecules and immune cells between compartments, making them central to drug absorption, toxicity, and inflammation. By assembling reproducible chips with human cells, researchers can study how a therapy affects a tissue under conditions that more closely approximate human biology than many animal models. The design also makes it possible to modify individual components for different organs or disease settings.
A major feature of the Rochester system is the integration of sensors directly into the chips. Developed in part through the work of biomedical engineering professor Benjamin Miller, these sensors can track barrier function and inflammatory signaling in real time. Instead of waiting until the end of an experiment to examine damaged cells, researchers can observe how a tissue responds as a drug is introduced. Changes in electrical or molecular signals may reveal that a barrier is becoming more permeable or that inflammatory pathways are being activated, providing an early warning of toxicity.
The immediate focus is on two severe complications associated with some cancer immunotherapies. Cytokine release syndrome, commonly called CRS, occurs when activated immune cells release large quantities of signaling proteins known as cytokines. The resulting systemic inflammation can cause fever, low blood pressure, breathing difficulties, and, in the most serious cases, organ failure. Immune effector cell-associated neurotoxicity syndrome, or ICANS, can affect the nervous system, producing confusion, seizures, impaired speech, or other neurological symptoms. Both conditions are difficult to predict reliably with animal testing because species differ in immune signaling networks and cell-surface receptors.
“The goal is to predict these toxicities from human cells on a chip, before a drug ever reaches a patient, and to do it without relying on animal models that have repeatedly failed to predict CRS in people,” says James McGrath, director of TraCe-bMPS and the William R. Kenan Jr. Professor of Biomedical Engineering. The approach does not simply attempt to reproduce a whole human body in miniature. Instead, it focuses on specific biological barriers and immune interactions that are directly relevant to the safety question being studied.
The project has now reached an important regulatory stage. The team was accepted into the US Food and Drug Administration’s Innovative Science and Technology Approaches for New Drugs, or ISTAND, pilot program. ISTAND is intended to help evaluate emerging methods that could improve drug development and eventually support regulatory decisions. Acceptance does not mean that the tissue-chip platform has already been approved for routine use, but it creates a formal pathway for the researchers to work with the FDA on defining the evidence needed for qualification.
The Rochester group is preparing a detailed qualification plan that will describe clinical considerations, timelines, data-sharing procedures, and statistical methods for evaluating the technology. If the platform ultimately receives FDA qualification, pharmaceutical companies could use its results as part of the evidence submitted in support of new drug applications. Such recognition would represent a significant step for organs-on-a-chip research, which has expanded rapidly but has only rarely progressed into formal regulatory programs.
The effort comes as US regulators seek alternatives to animal testing in preclinical safety studies. The FDA Modernization Act 2.0, enacted in 2022, opened the door for non-animal methods, while the agency’s 2025 roadmap outlined further efforts to reduce reliance on animal models. Researchers say pharmaceutical companies are showing strong interest because many immunotherapies are already in clinical development and carry risks of CRS or ICANS. The Rochester team collaborated with Graham Marsh of the Critical Path Institute and consulted with scientists at Pfizer about how the tool could fit into real-world drug development. If successful, the technology could give researchers a more human-relevant way to identify dangerous immune reactions early, helping developers eliminate unsafe candidates and refine promising treatments before patients are exposed.
Subject of Research: Human-cell tissue chips for predicting cancer immunotherapy toxicities.
Web References: University of Rochester; Translational Center for Barrier Microphysiological Systems; University of Rochester Biomedical Engineering; FDA ISTAND pilot program; FDA Modernization Act 2.0.
Image Credits: URochester photo / J. Adam Fenster.
Keywords: Drug discovery, tissue chips, organs-on-a-chip, cancer immunotherapy, cytokine release syndrome, CRS, ICANS, neurotoxicity, animal testing alternatives, biomedical engineering, microphysiological systems, human-cell models.
