Rabies virus glycoprotein 29 (RVG29) promotes CAR-T immunotherapy for glioma

  • Transl Res. 2023 Sep:259:1-12. doi: 10.1016/j.trsl.2023.03.003.
Feng Ji  1 ,  Luxia Xu  2 ,  Kaili Long  2 ,  Fan Zhang  2 ,  Miaomiao Zhang  2 ,  Xiao Lu  3 ,  Mingyue Xia  2 ,  Jiannan Chen  2 ,  Yu Du  2 ,  Yong Tang  4 ,  Heming Wu  4 ,  Yan Shi  4 ,  Ruiting Ma  2 ,  Jun Li  2 ,  Zhengliang Chen  2 ,  Bin Xu  5 ,  Qi Zhang  5 ,  Junqing Liang  6 ,  Shaochang Jia  7 ,  Zhigang Hu  8 ,  Zhigang Guo  9
Affiliations
  • 1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China; Zhongda Hospital, Southeast University, Nanjing, China. Electronic address: [email protected].
  • 2. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
  • 3. Xiamen University, Xiamen, China.
  • 4. Nanjing First Hospital, Nanjing, China.
  • 5. Zhongda Hospital, Southeast University, Nanjing, China.
  • 6. The Affiliated People's Hospital of Inner Mongolia Medical University, Inner Mongolia, China.
  • 7. Jinling Hospital of Nanjing University, Nanjing, China.
  • 8. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. Electronic address: [email protected].
  • 9. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. Electronic address: [email protected].
PMID: 36977441 DOI: 10.1016/j.trsl.2023.03.003
Abstract

Chimeric antigen receptor T cell (CAR-T) therapy has limited efficacy for treating glioma because of the infiltrative nature of the blood-brain barrier (BBB) and T cell exhaustion. Conjugation with rabies virus glycoprotein (RVG) 29 enhances the brain-related efficacy of various agents. Here we assess whether RVG enhances the ability of CAR-T cells to cross the BBB and improves their immunotherapy. We generated 70R CAR-T cells (anti-CD70 CAR-T modified with RVG29) and validated their tumor-killing efficacy in vitro and in vivo. We validated their effects on tumor regression in a human glioma mouse orthotopic xenograft model as well as in patient-derived orthotopic xenograft (PDOX) models. The signaling pathways activated in 70R CAR-T cells were revealed by RNA Sequencing. The 70R CAR-T cells we generated showed effective antitumor function against CD70+ glioma cells both in vitro and in vivo. 70R CAR-T cells were better able to cross the BBB into the brain than CD70 CAR-T cells under the same treatment conditions. Moreover, 70R CAR-T cells significantly promote the regression of glioma xenografts and improve the physical characteristics of mice without causing overt adverse effects. RVG modification enables CAR-T cells to cross the BBB, and stimulation with glioma cells induces 70R CAR-T cells to expand in a resting state. The modification of RVG29 has a positive impact on CAR-T therapy for brain tumors and may have potential in CAR-T therapy for glioma.

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