Development of a Novel CD26-Targeted Chimeric Antigen Receptor T-Cell Therapy for CD26-Expressing T-Cell Malignancies

Eiji Kobayashi; Yusuke Kamihara; Miho Arai; Akinori Wada; Shohei Kikuchi; Ryo Hatano; Noriaki Iwao; Takeshi Susukida; Tatsuhiko Ozawa; Yuichi Adachi; Hiroyuki Kishi; Nam H Dang; Taketo Yamada; Yoshihiro Hayakawa; Chikao Morimoto; Tsutomu Sato

doi:10.3390/cells12162059

Development of a Novel CD26-Targeted Chimeric Antigen Receptor T-Cell Therapy for CD26-Expressing T-Cell Malignancies

Cells. 2023 Aug 14;12(16):2059. doi: 10.3390/cells12162059.

Authors

Affiliations

¹ Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
² Department of Hematology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
³ Department of Pediatrics, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
⁴ Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
⁵ Department of Hematology, Juntendo University Shizuoka Hospital, Izunokuni City, Shizuoka 410-2211, Japan.
⁶ Division of Host Defences, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
⁷ Division of Hematology/Oncology, University of Florida, Gainesville, FL 32610-0275, USA.
⁸ Department of Pathology, Saitama Medical University, 38 Morohongo, Moroyama, Saitama 3500495, Japan.

Abstract

Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.

Keywords: CAR-T; CD26; T-cell malignancies; fratricide; third-generation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal
CD28 Antigens
Cell- and Tissue-Based Therapy
Dipeptidyl Peptidase 4
Lymphoma, T-Cell*
Mice
Receptors, Chimeric Antigen*
T-Lymphocytes

Substances

Receptors, Chimeric Antigen
CD28 Antigens
Dipeptidyl Peptidase 4
Antibodies, Monoclonal

Grants and funding

This research was supported by Japan Science and Technology Agency (JST) Moonshot R&D Grant Number JPMJMS2021, Japan Agency for Medical Research and Development (AMED) Grant Number 21lm0203005j0005 (A145), 22ym0126807j0001 (A160), 21am0401024h0003, and Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research Grant Number 21K07237, 21H02782.