Molecular therapy oncolytics | VOL. 25
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Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors.

Publication Date Jun 16, 2022

Abstract

Chimeric antigen receptor (CAR) Tcells targeting glypican-3 (GPC3) demonstrated early signs of therapeutic efficacy to hepatocellular carcinoma patients with a risk of cytokine release syndrome (CRS). Several adoptive cell therapies (ACTs) with Tcells using the natural Tcell receptor (TCR) signaling induced more efficient antitumor function and reduced cytokine production relative to CARs in solid tumors. To improve the efficacy and safety of GPC3-targeted ACTs, Tcells were modified with anti-GPC3 single-chain fragment variable(sFv) linked to CD3ε, which could be incorporated into the entire TCR/CD3 complex to form chimeric sFv-CD3ε receptor (sFv-ε). sFv-ε Tcells showed competitive antitumor activity and lower cytokine release compared to 28ζ or BBζ CAR Tcells, which may be ascribed to moderately less activated Ca2+-calcineurin-NFAT signaling pathway. We further generated murine sFv-ε Tcells with interleukin-7 co-expression (7sFv-ε) to promote Tcell survival and to mobilize the endogenous immune system. In immunocompetent mouse models, 7sFv-ε Tcells showed superior persistence, antitumor efficacy, and immunological memory while preserving the low production of cytokines associated with CRS compared to conventional sFv-ε Tcells. These results indicate that GPC3-specific 7sFv-ε Tcells could serve as a promising therapeutic strategy for solid tumors.

Concepts
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Chimeric Antigen Receptor
Risk Of Cytokine Release Syndrome
Cytokine Release Syndrome
calcineurin-NFAT Signaling Pathway
Natural T Cell Receptor
Adoptive Cell Therapies
Immunocompetent Mouse Models
Solid Tumors
Glypican-3
Immunological Memory

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