Development of Innate-Immune-Cell-Based Immunotherapy for Adult T-Cell Leukemia–Lymphoma

Author:

Nakashima Maho1,Tanaka Yoshimasa2ORCID,Okamura Haruki3,Kato Takeharu4,Imaizumi Yoshitaka5,Nagai Kazuhiro6,Miyazaki Yasushi7,Murota Hiroyuki18

Affiliation:

1. Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan

2. Center for Medical Innovation, Nagasaki University, Nagasaki 852-8588, Japan

3. Department of Tumor Cell Therapy, Hyogo College of Medicine, Nishinomiya 663-8501, Japan

4. Department of Hematology, Nagasaki University Hospital, Nagasaki 852-8501, Japan

5. Department of Hematology, National Hospital Organization Nagasaki Medical Center, Omura 856-8562, Japan

6. Department of Clinical Laboratory, National Hospital Organization Nagasaki Medical Center, Omura 856-8562, Japan

7. Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan

8. Leading Medical Research Core Unit, Life Science Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan

Abstract

γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia–lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.

Funder

JST START University Ecosystem Promotion Type (Supporting the Creation of Startup Ecosystems in Startup Cities), Japan

Grants-in-Aid for Scientific Research from MEXT

Grants-in-Aid for Scientific Research from the Japan Agency for Medical Research and Development

Research Funding granted by Nagasaki University President Shigeru Kohno

Publisher

MDPI AG

Subject

General Medicine

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3