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A digital shadow of CAR T cell expansion in a perfusion bioreactor: Informing optimal harvest times for autologous cell therapy

Egan, Joseph R., Marí‐Buyé, Núria, Benítez‐Cano, Elia Vallejo, Costa, Miquel, Wanika, Linda, Chappell, Michael J., Schultz, Ursula, Ochs, Jelena +4 more·2025·Biotechnology Progress
DOI 10.1002/btpr.70045PMC PMC12696450
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Abstract

Chimeric antigen receptor (CAR) T cell therapy has tremendous potential for the treatment of cancer and other diseases. To manufacture cells of the desired quantity and quality, it is important to expand the CAR T cells ex vivo for an optimal duration. However, identifying the optimal harvest time requires knowledge of the cell concentration during the expansion period. To address this challenge, we have developed a digital shadow of CAR T cell expansion that provides a soft sensor of cell concentration in real‐time. Specifically, a novel mechanistic mathematical model of cell growth within a proportional‐integral‐derivative (PID) controlled perfusion bioreactor has been developed using nonlinear ordinary differential equations. The model is fitted to data generated via bioreactor runs of the Aglaris FACER, in which both donor and patient cells have been expanded in two different media. Off‐line data includes the initial and final cell concentrations, and online data includes the glucose and lactate concentrations as well as the perfusion rate. Training the digital shadow utilizes all the off‐line and online data for each run. In contrast, real‐time testing utilizes only the initial cell concentration and the available online data at the time of model fitting. Real‐time testing shows that with at least 2.5 days of online data, the final cell concentration up to 2.5 days later is predicted with a mean relative error of 13% (standard deviation ≈ 6%). Informative real‐time predictions of cell concentration via the digital shadow can guide decisions regarding the optimal harvest time of CAR T cells.

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  • Egan et al. (2025) reported a Digital Shadow for CAR T cell expansion in perfusion culture, enabling soft sensor estimation of cell concentration and optimal harvest timing with a mean relative error of 13%.

    “Egan et al. (2025) reported a DS for CAR T cell expansion in perfusion culture, enabling soft sensor estimation of cell concentration and optimal harvest timing with a mean relative error of 13% [11].”

    From Mechanistic model for HEK293 viral vector processes and its application in a digital shadow framework (2026) · cites this paper as [11]

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Cited by

Sorted by citations

Authors
Egan, J. R., Marí‐Buyé, N., Benítez‐Cano, E. V., Costa, M., Wanika, L., Chappell, M. J., Schultz, U., Ochs, J., Effenberger, M., Horna, D., Rafiq, Q., & Goldrick, S.
Affiliations
  • Department of Biochemical Engineering University College London London UK
  • Aglaris Cell Tres Cantos Spain
  • School of Engineering University of Warwick Coventry UK
  • Sartorius CellGenix GmbH Freiburg Germany
ORCID
Egan, Joseph R.
Venue
Biotechnology Progress
Publisher
Wiley
Published
2025-06-23
Volume
41
Issue
6
ISSN
  • 8756-7938
  • 1520-6033
DOI
10.1002/btpr.70045
PMC
PMC12696450
Cited by
11
References
4
Language
en
Licence
Funders
  • Engineering and Physical Sciences Research Council (EP/P006485/1, EP/Z532770/1)
  • HORIZON EUROPE Framework Programme (101016909)
  • Innovate UK (830121)

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