Details

Autor(en) / Beteiligte

• Okada, Satomi
• Muraoka, Daisuke
• Yasui, Kiyoshi
• Tawara, Isao
• Kawamura, Ayumi
• Okamoto, Sachiko
• Mineno, Junichi
• Seo, Naohiro
• Shiku, Hiroshi
• Eguchi, Susumu
• Ikeda, Hiroaki

Titel

T cell receptor gene‐modified allogeneic T cells with siRNA for endogenous T cell receptor induce efficient tumor regression without graft‐versus‐host disease

Ist Teil von

• Cancer science, 2023-11, Vol.114 (11), p.4172-4183

Ort / Verlag

Tokyo: John Wiley & Sons, Inc

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Wiley Online Library

Beschreibungen/Notizen

• Abstract Adoptive immunotherapy using genetically engineered patient‐derived lymphocytes to express tumor‐reactive receptors is a promising treatment for malignancy. However, utilization of autologous T cells in this therapy limits the quality of gene‐engineered T cells, thereby inhibiting the timely infusion of the cells into patients. In this study, we evaluated the anti‐tumor efficacy and the potential to induce graft‐versus‐host disease (GVHD) in T cell receptor (TCR) gene‐engineered allogeneic T cells that downregulate the endogenous TCR and HLA class I molecules with the aim of developing an “off‐the‐shelf” cell product with expanded application of genetically engineered T cells. We transduced human lymphocytes with a high‐affinity TCR specific to the cancer/testis antigen NY‐ESO‐1 using a novel retrovirus vector with siRNAs specific to the endogenous TCR (siTCR vector). These T cells showed reduced expression of endogenous TCR and minimized reactivity to allogeneic cells in vitro. In non‐obese diabetic/SCID/γc null mice, TCR gene‐transduced T cells induced tumor regression without development of GVHD. A lentivirus‐based CRISPR/Cas9 system targeting β‐2 microglobulin in TCR gene‐modified T cells silenced the HLA class I expression and prevented allogeneic CD8 + T cell stimulation without disrupting their anti‐tumor capacity. This report is the first demonstration that siTCR technology is effective in preventing GVHD. Adoptive cell therapy with allogeneic T cells engineered with siTCR vector may be useful in developing an “off‐the‐shelf” therapy for patients with malignancy.