Systemic administration of mesenchymal stem cells loaded with a novel oncolytic adenovirus carrying a bispecific T cell engager against hepatocellular carcinoma

ABSTRACT

We previously established a hepatocellular carcinoma (HCC) targeting system of conditionally replicative adenovirus (CRAd) delivered by human umbilical cord-derived mesenchymal stem cells (HUMSCs). However, this system needed to be developed further to enhance the antitumor effect and overcome the limitations caused by the alpha-fetoprotein (AFP) heterogeneity of HCC. In this study, a bispecific T cell engager (BiTE) targeting programmed death ligand 1 controlled by the human telomerase reverse transcriptase promoter was armed on the CRAd of the old system. It was demonstrated on orthotopic transplantation model mice that the new system had a better anti-tumor effect with no more damage to extrahepatic organs and less liver injury, and the infiltration and activation of T cells were significantly enhanced in the tumor tissues of the model mice treated with the new system. Importantly, we confirmed that the new system eliminated the AFP-negative cells on AFP heterogeneous tumor models efficiently. Conclusion: Compared with the old system, the new system provided a more effective and safer strategy against HCC.

KEYWORDS:

• AFP
• BiTE
• Crad
• HCC
• hepatic differentiation
• HUMSC
• PBMC
• PD-L1
• tumor heterogeneity

Abbreviations

HCC: Hepatocellular carcinoma; CRAd: Conditionally replicative adenovirus; HUMSC: Human umbilical cord – derived mesenchymal stem cell; AFP: Alpha-fetoprotein; BiTE: Bispecific T cell engager; scFv: Single-chain variable fragment; PD-L1: Programmed death ligand 1; hTERT: Human telomerase reverse transcriptase; PCR: Polymerase chain reaction; ALT: Alanine aminotransferase; AST: Aspartate transaminase; IVIS: In Vivo Imaging System; MOI: Multiplicity of infection; ELISA: Enzyme-linked immune sorbent assay; PBMC: Peripheral blood mononuclear cell;

Authors’ contributions

XY wrote the main manuscript and designed and performed all the experiments. YL constructed the adenoviruses, established the stable expression cell line, and participated in animal operation. YY prepared all figures, performed electron microscope assay, and participated in animal operation. WT contributed to H&E staining and confocal microscopic imaging. YY and DF participated in the isolation of PBMCs and HUMSCs. RL assisted in FACS. XL performed Western blotting and luciferase assays. YX helped in ELISA. LY participated in cytotoxicity experiments. SY and DX were the corresponding authors; they participated in the design of the study and revised the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All animal studies were performed following the guidelines from the Animal Ethics Committee of the Tianjin NanKai Hospital.

Data Availability statement

The dataset supporting the conclusions of this study is included in the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2219544

Additional information

Funding

This study was supported by the Tianjin Municipal Science and Technology Commission Grant (Grant No. 19JCZDJC33100); the National Natural Science Foundation of China (Grant Nos . 82003266 and 81830005); CAMS Innovation Fund for Medical Sciences (Grant No. 2021-I2M-1-041); Haihe Laboratory of Cell Ecosystem Innovation Fund (Grant No. HH22KYZX0032); Scientific Foundation of Tianjin Municipal Education Commission (Grant No. 2019KJ196).