Anti-PD-1 antibody armored γδ T cells enhance anti-tumor efficacy in ovarian cancer
Yue Wang 1, Jingyi Han 1 2, Dongdong Wang
1, Menghua Cai 1, Yi Xu 1, Yu Hu 1, Hui Chen 1 3 4, Wei He 5, Jianmin Zhang 6 7
8
Signal Transduct Target Ther.2023 Oct
20;8(1):399. doi: 10.1038/s41392-023-01646-7.
PMID: 37857598
Abstract
γδ T cells have the unique ability to detect a wide range of tumors
with low mutation burdens, making them attractive candidates for CAR-T-cell
therapy. Unlike αβ T cells and other immune cells, γδ T cells are superior in
MHC non-restriction, selective cell recruitment, and rapid activation. However,
clinical trials have shown limited clinical benefits, and the adoptive
transplantation of γδ T cells has often fallen short of expectations. We
hypothesized that the limited effectiveness of γδ T cells in eradicating tumor
cells may be attributed to the inhibitory tumor microenvironment induced by the
suppressive PD-1/PD-L1 axis. Herein, we constructed novel armored γδ T cells
capable of secreting humanized anti-PD-1 antibodies, referred to as
"Lv-PD1-γδ T cells. Lv-PD1-γδ T cells showed improved proliferation and
enhanced cytotoxicity against tumor cells, resulting in augmented therapeutic
effects and survival benefits in ovarian tumor-bearing mice. These engineered
cells demonstrated a prolonged in vivo survival of more than 29 days, without
any potential for tumorigenicity in immunodeficient NOD/SCID/γ null mice. We
also found that Lv-PD1-γδ T cells exhibited excellent tolerance and safety in
humanized NOD/SCID/γ null mice. With attenuated or eliminated immunosuppression
and maximized cytotoxicity efficacy by the local secretion of anti-PD1
antibodies in tumors, Lv-PD1-γδ T cells can serve as a promising
"off-the-shelf" cell therapy against cancers.