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

Author:

Okada Satomi12ORCID,Muraoka Daisuke13ORCID,Yasui Kiyoshi1,Tawara Isao4,Kawamura Ayumi5,Okamoto Sachiko5,Mineno Junichi5,Seo Naohiro67ORCID,Shiku Hiroshi6,Eguchi Susumu2,Ikeda Hiroaki18ORCID

Affiliation:

1. Department of Oncology Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan

2. Department of Surgery Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan

3. Division of Translational Oncoimmunology Aichi Cancer Center Research Institute Nagoya Japan

4. Department of Hematology and Oncology Mie University Graduate School of Medicine Mie Japan

5. Takara Bio Inc. Shiga Japan

6. Department of Personalized Cancer Immunotherapy Mie University Graduate School of Medicine Mie Japan

7. Department of Bioengineering, School of Engineering The University of Tokyo Tokyo Japan

8. Leading Medical Research Core Unit Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan

Abstract

AbstractAdoptive 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/γcnull 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.

Funder

Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

Publisher

Wiley

Subject

Cancer Research,Oncology,General Medicine

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