1. Rational design of PD-1-CD28 immunostimulatory fusion proteins for CAR T cell therapy.
- Author
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Lorenzini T, Cadilha BL, Obeck H, Benmebarek MR, Märkl F, Michaelides S, Strzalkowski T, Briukhovetska D, Müller PJ, Nandi S, Winter P, Majed L, Grünmeier R, Seifert M, Rausch S, Feuchtinger T, Endres S, and Kobold S
- Subjects
- Humans, Mice, Animals, CD28 Antigens, Programmed Cell Death 1 Receptor, B7-H1 Antigen, Cell Line, Tumor, Immunotherapy, Adoptive, Leukemia
- Abstract
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., (© 2023. The Author(s).)- Published
- 2023
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