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Lesch, S.* ; Nottebrock, A.* ; Rataj, F.* ; Heise, C.* ; Endres, S. ; Kobold, S.

PD-1-CD28 fusion protein strengthens mesothelin-specific TRuC T cells in preclinical solid tumor models.

Cell Oncol., DOI: 10.1007/s13402-022-00747-9 (2022)
Publ. Version/Full Text Research data DOI PMC
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Background: T cell receptor fusion constructs (TRuC) consist of an antibody-based single chain variable fragment (scFv) fused to a T cell receptor chain (TCR) and allow recognition of cancer cells in an HLA-independent manner. Unlike chimeric antigen receptors (CAR), TRuC are integrated into the TCR complex resulting in a functional chimera with novel specificity, whilst retaining TCR signaling. To further enhance anti-tumor function, we expressed a PD-1-CD28 fusion receptor in TRuC T cells aiming to prevent tumor-induced immune suppression and T cell anergy. Methods: The activation level of engineered T cells was investigated in co-culture experiments with tumor cells followed by quantification of released cytokines using ELISA. To study T cell-mediated tumor cell lysis in vitro, impedance-based real-time tumor cell killing and LDH release was measured. Finally, two xenograft mouse cancer models were employed to explore the therapeutic potential of engineered T cells. Results: In co-culture assays, co-expression of PD-1-CD28 enhanced cytokine production of TRuC T cells. This effect was dependent on PD-L1 to PD-1-CD28 interactions, as blockade of PD-L1 amplified IFN-γ production in unmodified TRuC T cells to a greater level compared to TRuC-PD-1-CD28 T cells. In vivo, PD-1-CD28 co-expression supported the anti-tumor efficacy of TRuC T cells in two xenograft mouse cancer models. Conclusion: Together, these results demonstrate the therapeutic potential of PD-1-CD28 co-expression in TRuC T cells to prevent PD-L1-induced T cell hypofunction.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adoptive Cell Transfer ; Immunosuppression ; Pd-1-cd28 Fusion Protein ; T Cell Hypofunction ; Truc T Cells
ISSN (print) / ISBN 2211-3428
e-ISSN 2211-3436
Journal Cellular Oncology
Publisher Springer
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)