GD2-specific chimeric antigen receptor-modified T cells targeting retinoblastoma - assessing tumor and T cell interaction

Jatuporn Sujjitjoon; Elias Sayour; Shih-Ting Tsao; Mongkol Uiprasertkul; Kleebsabai Sanpakit; Jassada Buaboonnam; Pa-Thai Yenchitsomanus; La-Ongsri Atchaneeyasakul; Lung-Ji Chang

doi:10.1016/j.tranon.2020.100971

GD2-specific chimeric antigen receptor-modified T cells targeting retinoblastoma - assessing tumor and T cell interaction

Transl Oncol. 2021 Feb;14(2):100971. doi: 10.1016/j.tranon.2020.100971. Epub 2020 Dec 13.

Authors

Jatuporn Sujjitjoon¹, Elias Sayour², Shih-Ting Tsao³, Mongkol Uiprasertkul⁴, Kleebsabai Sanpakit⁵, Jassada Buaboonnam⁵, Pa-Thai Yenchitsomanus⁶, La-Ongsri Atchaneeyasakul⁷, Lung-Ji Chang⁸

Affiliations

¹ Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok 10700, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
² University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, Florida, United States.
³ Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States; Shenzhen Geno-Immune Medical Institute, 2nd FL. 6 Yuexing 2nd Rd., Nanshan Dist., Shenzhen, China.
⁴ Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁵ Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁶ Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok 10700, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Electronic address: pathai.yen@mahidol.edu.
⁷ Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Electronic address: laongsri.ath@mahidol.ac.th.
⁸ Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States; Shenzhen Geno-Immune Medical Institute, 2nd FL. 6 Yuexing 2nd Rd., Nanshan Dist., Shenzhen, China; School of Medicine, University of Electronic Science and Technology of China, Sichuan, China. Electronic address: c@szgimi.org.

Abstract

A novel disialoganglioside 2 (GD2)-specific chimeric antigen receptor (CAR)-modified T cell therapy against retinoblastoma (RB) were generated. GD2-CAR consists of a single-chain variable fragment (scFv) derived from a monoclonal antibody, hu3F8, that is linked with the cytoplasmic signaling domains of CD28, 41BB, a CD3ζ, and an inducible caspase 9 death fusion partner. GD2 antigen is highly expressed in Y79RB cell line and in several surgical RB tumor specimens. In vitro co-culture experiments revealed the effective killing of Y79RB cells by GD2-CAR T cells, but not by control CD19-CAR T cells. The killing activities of GD2-CAR T cells were diminished when repeatedly exposed to the tumor, due to an attenuated expression of GD2 antigen on tumor cells and upregulation of inhibitory molecules of the PD1 and PD-L1 axis in the CAR T cells and RB tumor cells respectively. This is the first report to describe the potential of GD2-CAR T cells as a promising therapeutic strategy for RB with the indication of potential benefit of combination therapy with immune checkpoint inhibitors.

Keywords: Chimeric antigen receptor T cells; Disialoganglioside 2; GD2; Retinoblastoma.