Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

CAR-Modified Vγ9Vδ2 T Cells Propagated Using a Novel Bisphosphonate Prodrug for Allogeneic Adoptive Immunotherapy

Yizheng Wang
,
Linan Wang
,
Naohiro See
ORCID logo ,
Satoshi Okumura
,
Tae Hayashi
,
Yasushi Akahori
,
Hiroshi Fujiwara
,
Yasunori Amaishi
,
Sachiko Amaishi
,
Junichi Mineno
,
Yoshimasa Tanaka
ORCID logo ,
Takuma Kato
*
Version 1 : Received: 25 May 2023 / Approved: 26 May 2023 / Online: 26 May 2023 (04:45:32 CEST)

A peer-reviewed article of this Preprint also exists.

Wang, Y.; Wang, L.; Seo, N.; Okumura, S.; Hayashi, T.; Akahori, Y.; Fujiwara, H.; Amaishi, Y.; Okamoto, S.; Mineno, J.; Tanaka, Y.; Kato, T.; Shiku, H. CAR-Modified Vγ9Vδ2 T Cells Propagated Using a Novel Bisphosphonate Prodrug for Allogeneic Adoptive Immunotherapy. Int. J. Mol. Sci. 2023, 24, 10873. Wang, Y.; Wang, L.; Seo, N.; Okumura, S.; Hayashi, T.; Akahori, Y.; Fujiwara, H.; Amaishi, Y.; Okamoto, S.; Mineno, J.; Tanaka, Y.; Kato, T.; Shiku, H. CAR-Modified Vγ9Vδ2 T Cells Propagated Using a Novel Bisphosphonate Prodrug for Allogeneic Adoptive Immunotherapy. Int. J. Mol. Sci. 2023, 24, 10873.

Abstract

CAR-T therapy has achieved considerable treatment success in hematologic tumors by using patient derived autologous αβ T cells. There is an impetus to broaden the applicability of this approach by using a third-party donor derived CAR-T cell product which has a potent anti-tumor function but a constrained GVHD property. In this study, CAR-T cells were prepared from Vγ9Vδ2 T cells expanded by using a novel prodrug PTA and their anti-tumor functions were assessed in conjunction with persistency, localization, and phenotype. γδ T cells were successfully transduced with a CAR specific to CEA with signaling domains of CD3ζ and CD28 (CEA.CAR-γδ T cells), and exhibited potent tumor killing function in vitro. In a xenograft mouse model, CEA.CAR-γδ T cells suppressed CEA+ tumor growth though a limited time window. CEA.CAR-γδ T cells persisted and accumulated in the tumor even after tumor progression, however, ex vivo analysis revealed that those recovered at different time points from PBMC, spleen and tumors gradually lost tumor reactivity as assessed by IFN-γ production. Provision of GITR co-stimulation enhanced anti-tumor function of CEA.CAR-γδ T cells, the result of which imposes additional measurers to be adopted in CAR-γδ T cells for an allogeneic adoptive immunotherapy.

Keywords

CAR-T; CEA, γδ-T cell; off-the-shelf; GITR signaling

Subject

Biology and Life Sciences, Immunology and Microbiology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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