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Guaza-Lasheras, M.* ; Nimmerfroh, J.* ; Schwarz, D.* ; Grujil, T.D.d.* ; Hartmann, J.* ; Klein, C.* ; Läubli, H.* ; Lotem, M.* ; Mittelstaet, J.* ; Paget, C.* ; Hadrup, S.R.* ; Schallenberg, S.* ; Straten, P.t.* ; Theurich, S.* ; Venetz, D.* ; Zippelius, A.* ; Zitvogel, L.* ; Kobold, S.

The evolving role of cytokines for CAR-T cell manufacturing and beyond.

Nat. Bio. Eng., DOI: 10.1038/s41551-026-01703-w (2026)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Chimeric antigen receptor (CAR)-T cells represent a recent clinically validated modality in cancer therapy and beyond. However, broad industrial implementation faces technological, logistical, regulatory and financial challenges. A major bottleneck is the ex vivo production process, where cytokines are essential and product-determining constituents. To better understand the complexity of cytokine utilization throughout the production process, we rigorously reviewed the existing literature, including extended manufacturing parameters from 292 available clinical reports. We found a progressive reduction of interleukin-2 exposure, driven by its association with unfavourable cell characteristics. Preclinically, this catalysed the evaluation of alternative cytokines with potential to preserve naive phenotypes, support cell expansion and enhance the efficacy of CAR-T cells. Here we illustrate the evolving use of cytokines, reveal non-standardized clinical CAR-T cell manufacturing parameters, and summarize preclinical and next-generation concepts, which may improve manufacturing efficiency, cost-effectiveness and therapeutic outcomes. Our observations may further guide the development of cytokine-armouring strategies to promote in-patient expansion and persistence, even as innovations such as shortened manufacturing and in vivo engineering techniques could reduce reliance on cytokines during ex vivo culture.
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Publication type Article: Journal article
Document type Review
Keywords Perspective (graphical) ; Cytokine ; Cell ; Manufacturing Process ; Clinical Trial ; Cellular Manufacturing ; Good Manufacturing Practice; Memory Stem-cells; Monoclonal-antibodies; Il-2 Receptor; Ex-vivo; In-vivo; Antigen; Therapy; Lymphocytes; Activation; Expansion
ISSN (print) / ISBN 2157-846X
e-ISSN 2157-846X
Journal Nature biomedical engineering
Publisher Nature Publishing Group
Publishing Place London ; New York NY ; Tokyo
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)
Grants This study was supported by the Bavarian Cancer Research Center (BZKF) (TANGO to S.K.), the Deutsche Forschungsgemeinschaft (DFG, grant number: KO5055-2-1 and KO5055/3-1 to S.K.), the international doctoral program 'i-Target: immunotargeting of cancer' (f
odowska-Curie Actions)
odowska-Curie Actions (H2020 Excellent Science - Marie Sklstrok
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Sklstrok