title: Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome.
abstract: Carcinoembryonic antigen (CEA) is a cell surface antigen highly expressed in various cancer cell types and in healthy tissues. It has the potential to be a target for chimeric antigen receptor (CAR)-modified T-cell therapy; however, the safety of this approach in terms of on-target/off-tumor effects needs to be determined. To address this issue in a clinically relevant model, we used a mouse model in which the T cells expressing CEA-specific CAR were transferred into tumor-bearing CEA-transgenic (Tg) mice that physiologically expressed CEA as a self-antigen. The adoptive transfer in conjunction with lymphodepleting and myeloablative preconditioning mediated significant tumor regression but caused weight loss in CEA-Tg, but not in wild-type mice. The weight loss was not associated with overt inflammation in the CEA-expressing gastrointestinal tract but was associated with malnutrition, reflected in elevated systemic levels of cytokines linked to anorexia, which could be controlled by the administration of an anti-IL-6 receptor monoclonal antibody without compromising efficacy. The apparent relationship between lymphodepleting and myeloablative preconditioning, efficacy, and off-tumor toxicity of CAR-T cells would necessitate the development of CEA-specific CAR-T cells with improved signaling domains that require less stringent preconditioning for their efficacy. Taken together, these results suggest that CEA-specific CAR-based adoptive T-cell therapy may be effective for patients with CEA+solid tumors. Distinguishing the fine line between therapeutic efficacy and off-tumor toxicity would involve further modifications of CAR-T cells and preconditioning regimens.
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine , Tsu, Mie, Japan.
authors.forename: Linan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Faculty of Nursing Science, Suzuka Medical Science University , Suzuka, Mie, Japan.
authors.forename: Ning
authors.initials: N
authors.lastname: Ma
authors.affiliation: Takara Bio, Inc. , Shiga, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Takara Bio, Inc. , Shiga, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Amaishi
authors.affiliation: Department of Pathology, Institute of Medical Science, Medical Research Center, Tokyo Medical University , Tokyo, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine , Tsu, Mie, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Seo
authors.affiliation: Takara Bio, Inc. , Shiga, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Mineno
authors.affiliation: Department of Pathology, Institute of Medical Science, Medical Research Center, Tokyo Medical University , Tokyo, Japan.
authors.forename: Kazutoh
authors.initials: K
authors.lastname: Takesako
authors.affiliation: Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Mie, Japan; Center for Comprehensive Cancer Immunotherapy, Mie University, Tsu, Mie, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan; Center for Comprehensive Cancer Immunotherapy, Mie University, Tsu, Mie, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
keywords: Adoptive T-cell therapy; carcinoembryonic antigen; chimeric antigen receptor; cytokine release syndrome; neurotoxicity; preconditioning