| Author |
Miyazaki T, Murayama Y, Oike N, Baba M, Kasahara Y, Shin C, Kubo N, Ariizumi T, Suzuki Y, Mihara K, Ling Y, Okuda S, Saitoh A, Imamura M, Ogose A, Kawashima H, Imai C.
|
| Abstract |
The prognosis for advanced synovial sarcoma remains poor, with limited therapeutic options. Recently, cloned T cell receptor (TCR)-engineered T cell therapy has shown promising results in patients with advanced synovial sarcoma; however, the number of patients eligible for this therapy is limited owing to human leukocyte antigen (HLA) restriction. To solve this problem, we focused on chimeric antigen receptor (CAR)-T cells that target ligands of NKG2D, an activating receptor of natural killer cells. Because NKG2D recognizes a family of eight ligands, we hypothesized that NKG2D-based CARs could function as an intrinsic multi-antigen targeting platform, potentially mitigating antigen heterogeneity and antigen escape, which are key barriers in CAR-T therapy for solid tumors. We first evaluated the surface expression of NKG2D ligands (NKG2DLs) in synovial sarcoma cell lines and examined their transcript levels in public bulk RNA-seq datasets from synovial sarcoma tissues. We then constructed NKG2D-based, 4-1BB-co-stimulated CAR-T cells. These CAR-T cells showed effector responses and antitumor effects against synovial sarcoma cells in vitro, as demonstrated by the results of the intracellular cytokine production, cytokine secretion, CD107a degranulation assay, WST-8 assay, and real-time cell analysis, and in vivo in an NSG mouse xenograft model of synovial sarcoma. Although further mechanistic, translational, and safety validation studies are required, these findings provide a preliminary disease-specific preclinical proof of concept for HLA-independent NKG2D-based CAR-T cell therapy in synovial sarcoma, particularly in patients who are ineligible for or have not responded to TCR-T therapy.
|
