IMR Press / FBL / Volume 23 / Issue 12 / DOI: 10.2741/4703

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article

GITR domain inside CAR co-stimulates activity of CAR-T cells against cancer

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1 Promab Biotechnologies, 2600 Hilltop Drive, Building B, Richmond, CA 94806, USA
2 GenoImmune/ BGI’s company, Beishan Industrial Zone, Shenzhen, 518083, China
3 Hunan Forevertek Biotechnology, Changsha, Co., Ltd, China
Front. Biosci. (Landmark Ed) 2018, 23(12), 2245–2254; https://doi.org/10.2741/4703
Published: 1 June 2018
(This article belongs to the Special Issue Focal adhesion signaling in cancer)
Abstract

T cells expressing Chimeric antigen receptors or CAR-T cells are used as a novel treatment against hematological and solid cancers. In this report, we designed CAR with glucocorticoid-induced TNFR-related protein (GITR) co-stimulatory domain to study its ability to co-activate CAR-T cells. EGFR-GITR-CD3 CAR-T cells were cytotoxic against EGFR-positive: pancreatic and ovarian cancer cells but not against EGFR-negative cancer cells. The cytotoxic activity of EGFR-GITR-CD3 CAR-T cells was comparable or better than EGFR-28-CD3 or EGFR-41BB-CD3 CAR-T cells. We designed also EGFR-CD3-GITR-CAR and EGFR-ΔGITR-CD3 with deleted 184-192 amino-acids of co-stimulatory GITR domain, and showed that EGFR-GITR-CD3 had significantly higher cytotoxic activity against EGFR-positive cells. The EGFR-GITR-CD3 cells secreted significantly higher levels of IFN-gamma than EGFR-CD3-GITR and EGFR-ΔGITR-CD3 cells. In addition, Mesothelin-GITR-CD3 CAR-T cells also killed mesothelin-positive ovarian cancer cell lines, and pancreatic cancer cells. Moreover, CD19-GITR-CD3 CAR-T cells had significant cytotoxic activity against CD19-positive cancer cells in vitro and in Raji xenograft tumors in vivo. Thus, our results clearly show that GITR co-stimulatory domain can be used as a novel co-stimulatory domain in CAR-T cells.

Keywords
Chimeric Antigen Receptor
Immunotherapy
Cancer
Cytokine
Cell
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