Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma.

Published on Mar 5, 2021in Molecular Therapy - Oncolytics4.115
· DOI :10.1016/J.OMTO.2021.03.001
Hiroshi Kubo1
Estimated H-index: 1
(Kyoto Prefectural University of Medicine),
Shigeki Yagyu14
Estimated H-index: 14
(Kyoto Prefectural University of Medicine)
+ 6 AuthorsHajime Hosoi33
Estimated H-index: 33
(Kyoto Prefectural University of Medicine)
Sources
Abstract
Abstract Ephrin type-B receptor 4 (EPHB4), expressed in tumors including rhabdomyosarcoma, is a suitable target for chimeric antigen receptor (CAR)-T cells. Ligand independent activation of EPHB4 causes cell proliferation and malignant transformation in rhabdomyosarcoma, whereas ligand-dependent stimulation of EPHB4 induces apoptosis in rhabdomyosarcoma. Therefore, we hypothesized that ligand-based EPHB4-specific CAR-T cells may kill rhabdomyosarcoma cells without stimulating downstream cell proliferation mechanisms. We developed novel CAR-T cells by targeting EPHB4 via EPHRIN B2, a natural ligand of EPHB4. Generating EPHB4-CAR-T cells via piggyBac transposon (PB)-based gene transfer resulted in sufficient T cell expansion and CAR positivity (78.5 ± 5.9 %). PB-EPHB4-CAR-T cells displayed a dominant stem cell memory fraction (59.4 ± 7.2 %) as well as low PD-1 expression (0.60 ± 0.21 %) after 14 d of expansion. The PB-EPHB4-CAR-T cells inhibited EPHB4-positive tumor cells without activating cell proliferation downstream of EPHB4, even after multiple tumor re-challenges, and suppressed tumor growth in xenograft-bearing mice. Therefore, PB-EPHB4-CAR-T cells possess a memory-rich fraction without early T cell exhaustion, and show potential as promising therapeutic agents for treating rhabdomyosarcoma and other EPHB4-positive tumors.
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