SMART develops efficient CAR T-cell production using microfluidic bioreactor

New Delhi: Researchers at the Singapore-MIT Alliance for Research and Technology (SMART) have pioneered the production of chimeric antigen receptor (CAR) T-cells using a high-density microfluidic bioreactor, marking a significant advancement in cancer treatment. 

In collaboration with Duke-NUS Medical School, the Institute of Molecular and Cell Biology (IMCB) at A*STAR, KK Women’s & Children’s Hospital, and Singapore General Hospital, the study demonstrates that CAR T-cells can be produced more efficiently and with fewer resources. Published in Nature Biomedical Engineering, the research shows the microfluidic bioreactor can produce over 60 million CAR T-cells from lymphoma patients and over 200 million from healthy donors.

This first demonstration of a micro bioreactor for autologous cell therapy highlights its efficiency, translating to lower manufacturing costs and potentially reducing patient costs. This method could lead to scalable, cost-effective production of CAR T-cells and enable point-of-care production outside laboratories.

Developed by the Critical Analytics for Manufacturing Personalized-Medicine (CAMP) Interdisciplinary Research Group (IRG) at SMART, the technique produces clinical doses of CAR T-cells on a microfluidic chip the size of a pack of cards, addressing contamination and human error issues in current processes. 

CAR T-cell therapy involves isolating, activating, genetically modifying, and expanding a patient’s T-cells to target tumor cells. Despite their revolutionary impact, CAR T-cell manufacturing remains inconsistent, costly, and time-consuming. The new method achieves similar T-cell numbers with a 30-40% shorter culture period (7-8 days) compared to traditional methods (12 days), with CAR T-cells showing only subtle differences in quality and equal effectiveness in killing leukaemia cells in mice.

“This new method suggests that a dramatic miniaturization of current-generation autologous cell therapy production is feasible, with the potential of significantly alleviating manufacturing limitations of CAR T-cell therapy,” said Wei-Xiang Sin, Research Scientist at SMART CAMP and first author of the paper. “Such a miniaturisation would lay the foundation for point-of-care manufacturing ofvCAR T-cells and decrease the “good manufacturing practice” (GMP) footprint required for producing cell therapies – which is one of the primary drivers of COGM.”

The microbioreactor, originally developed at MIT and advanced to commercial production by Millipore Sigma, is a perfusion-based, automated, closed system with the smallest footprint, culture volume, and seeding cell number, alongside the highest cell density and process control. It requires significantly lower volumes of medium, isolation beads, activation reagents, and lentiviral vectors, benefiting pediatric patients with low T-cell numbers.

Michael Birnbaum, Co-Lead Principal Investigator at SMART CAMP and Associate Professor of Biological Engineering at MIT, emphasized “This advancement in cell therapy manufacturing could ultimately offer a point-of-care platform that could substantially increase the number of CAR T-cell production slots, reducing the wait times and cost of goods of these living medicines – making cell therapy more accessible to the masses. The use of scaled-down bioreactors could also aid process optimisation studies, including for different cell therapy products.”

SMART CAMP continues to optimize process parameters and culture conditions to improve cell yield and quality for future clinical use. The research is supported by the National Research Foundation (NRF) Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) program.