Accurate control of dual-receptor-engineered T cell activity through a bifunctional anti-angiogenic peptide.

Abstract

BACKGROUND:

Chimeric antigen receptors (CARs) presented on T cell surfaces enable redirection of T cell specificity, which has enormous promise in antitumor therapy. However, excessive activity and poor control over such engineered T cells cause significant safety challenges, such as cytokine release syndrome and organ toxicities. To enhance the specificity and controllable activity of CAR-T cells, we report a novel switchable dual-receptor CAR-engineered T (sdCAR-T) cell and a new switch molecule of FITC-HM-3 bifunctional molecule (FHBM) in this study.

METHODS:

We designed a fusion molecule comprising FITC and HM-3. HM-3, an antitumor peptide including an Arg-Gly-Asp sequence, can specifically target integrin αvβ3 that is presented on some tumor cells. Moreover, to improve the specificity of CAR-T cells, we also generated the sdCAR-T cell line against cognate tumor cells expressing human mesothelin (MSLN) and integrin αvβ3. Finally, the activity of sdCAR-T cell and FHBM is verified via in vitro and in vivo experiments.

RESULTS:

In the presence of FHBM, the designed sdCAR-T cells exerted high activity including activation and proliferation and had specific cytotoxicity in a time- and dose-dependent manner in vitro. Furthermore, using a combination of FHBM in nude mice, sdCAR-T cells significantly inhibited the growth of MSLN+ K562 cells and released lower levels of the cytokines (e.g., interleukin-2, interferon γ, interleukin-6, and tumor necrosis factor α) relative to conventional CAR-T cells, obtaining specific, controllable, and enhanced cytotoxicity.

CONCLUSIONS:

Our data indicate that FHBM can accurately control timing and dose of injected CAR-T cells, and sdCAR-T cells exert significant antitumor activity while releasing lower levels of cytokines for the cognate tumor cells expressing both MSLN and integrin αvβ3. Therefore, combination therapies using sdCAR-T cells and the switch molecule FHBM have significant potential to treat malignancies.

• Authors: Erhao Zhang, Jieyi Gu, Jianpeng Xue, Chenyu Lin, Chen Liu, Mengwei Li, Jingchao Hao, Sarra Setrerrahmane, Xiaowei Chi, Weiyan Qi, Jialiang Hu, Hanmei Xu
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 11 Issue 1 Pg. 44 (03 20 2018) ISSN: 1756-8722 [Electronic] England
• PMID: 29558951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenic Proteins
• MSLN protein, human
• Msln protein, mouse
• Receptors, Chimeric Antigen
• Mesothelin

Topics

• Angiogenic Proteins (immunology)
• Animals
• Humans
• Mesothelin
• Mice
• Receptors, Chimeric Antigen (immunology)
• T-Lymphocytes (immunology)