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Lorenzini, T.* ; Cadilha, B.L.* ; Obeck, H.* ; Benmebarek, M.R.* ; Märkl, F.* ; Michaelides, S.* ; Strzalkowski, T.* ; Briukhovetska, D.* ; Müller, P.J.* ; Nandi, S.* ; Winter, P.* ; Majed, L.* ; Grünmeier, R.* ; Seifert, M.* ; Rausch, S.* ; Feuchtinger, T.* ; Endres, S. ; Kobold, S.

Rational design of PD-1-CD28 immunostimulatory fusion proteins for CAR T cell therapy.

Br. J. Cancer 129, 696-705 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Background: In many situations, the therapeutic efficacy of CAR T cells is limited due to immune suppression and poor persistence. Immunostimulatory fusion protein (IFP) constructs have been advanced as a tool to convert suppressive signals into stimulation and thus promote the persistence of T cells, but no universal IFP design has been established so far. We now took advantage of a PD-1-CD28 IFP as a clinically relevant structure to define key determinants of IFP activity. Methods: We compared different PD-1-CD28 IFP variants in a human leukemia model to assess the impact of distinctive design choices on CAR T cell performance in vitro and a xenograft mouse model. Results: We observed that IFP constructs that putatively exceed the extracellular length of PD-1 induce T-cell response without CAR target recognition, rendering them unsuitable for tumour-specific therapy. IFP variants with physiological PD-1 length ameliorated CAR T cell effector function and proliferation in response to PD-L1+ tumour cells in vitro and prolonged survival in vivo. Transmembrane or extracellular CD28 domains were found to be replaceable by corresponding PD-1 domains for in vivo efficacy. Conclusion: PD-1-CD28 IFP constructs must mimic the physiological interaction of PD-1 with PD-L1 to retain selectivity and mediate CAR-conditional therapeutic activity.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cd28 Costimulation; Pd-1; Blockade; Children; Efficacy; Express
ISSN (print) / ISBN 0007-0920
e-ISSN 1532-1827
Journal British Journal of Cancer BJC
Quellenangaben Volume: 129, Issue: 4, Pages: 696-705 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)