Molecular Therapy
Volume 30, Issue 2, 2 February 2022, Pages 534-549
Journal home page for Molecular Therapy

Original Article
Dual-antigen targeted iPSC-derived chimeric antigen receptor-T cell therapy for refractory lymphoma

https://doi.org/10.1016/j.ymthe.2021.10.006Get rights and content
Under a Creative Commons license
open archive

We generated dual-antigen receptor (DR) T cells from induced pluripotent stem cells (iPSCs) to mitigate tumor antigen escape. These cells were engineered to express a chimeric antigen receptor (CAR) for the antigen cell surface latent membrane protein 1 (LMP1; LMP1-CAR) and a T cell receptor directed to cell surface latent membrane protein 2 (LMP2), in association with human leucocyte antigen A24, to treat therapy-refractory Epstein-Barr virus-associated lymphomas. We introduced LMP1-CAR into iPSCs derived from LMP2-specific cytotoxic T lymphocytes (CTLs) to generate rejuvenated CTLs (rejTs) active against LMP1 and LMP2, or DRrejTs. All DRrejT-treated mice survived >100 days. Furthermore, DRrejTs rejected follow-up inocula of lymphoma cells, demonstrating that DRrejTs persisted long-term. We also demonstrated that DRrejTs targeting CD19 and LMP2 antigens exhibited a robust tumor suppressive effect and conferred a clear survival advantage. Co-operative antitumor effect and in vivo persistence, with unlimited availability of DRrejT therapy, will provide powerful and sustainable T cell immunotherapy.

Keywords

CD19-CAR
dual-antigen targeted CART therapy
EBV-associated lymphoma
iPSC-derived CTL
LMP1
LMP2
rejuvenated CTL
dual CAR
iPSC-CART
“off-the-shelf” T cell therapy

Cited by (0)

11

Co-senior authors