Page 282 - Haematologica March 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):796-807
Cell Therapy & Immunotherapy
Long-term eradication of extranodal natural killer/T-cell lymphoma, nasal type, by induced pluripotent stem cell-derived Epstein-Barr virus-specific rejuvenated T cells in vivo
Miki Ando,1,2 Jun Ando,1 Satoshi Yamazaki,2 Midori Ishii,1 Yumi Sakiyama,2 Sakiko Harada,1 Tadahiro Honda,1 Tomoyuki Yamaguchi,2 Masanori Nojima,3 Koichi Ohshima,4 Hiromitsu Nakauchi,2,5* and Norio Komatsu1*
1Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan;
2
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine,
The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 3Center for Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 4Department of Pathology, School of Medicine, Kurume University, Fukuoka, Japan and 5Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
ABSTRACT
Functionally rejuvenated induced pluripotent stem cell (iPSC)-derived antigen-specific cytotoxic T lymphocytes (CTL) are expected to be a potent immunotherapy for tumors. When L-asparaginase-containing standard chemotherapy fails in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), no effective salvage therapy exists. The clinical course then is miserable. We demonstrate prolonged and robust eradication of ENKL in vivo by Epstein-Barr virus-specific iPSC-derived antigen-specific CTL, with iPSC-derived antigen-specific CTL persisting as central memory T cells in the mouse spleen for at least six months. The anti-tumor response is so strong that any concomitant effect of the programmed cell death 1 (PD-1) blockade is unclear. These results suggest that long-term persistent Epstein-Barr virus-specific iPSC-derived antigen-specific CTL contribute to a continuous anti-tumor effect and offer an effective salvage therapy for relapsed and refractory ENKL.
Introduction
ENKL, a highly aggressive disease, is relatively common in Asia and South America. Necrosis is extensive and dissemination to various sites is rapid. The out- come is miserable.1,2 Expressing high concentrations of multidrug-resistance P-gly- coprotein, ENKL cells resist anthracycline-based standard chemotherapy.3 L- asparaginase selectively induces apoptosis in ENKL,4 and the L-asparaginase-con- taining regimen SMILE (dexamethasone [“steroids”], methotrexate, ifosfamide, L- asparaginase, etoposide) prolongs survival in advanced ENKL.5,6 However, even with SMILE, 5-year overall survival is 47%.5 No effective salvage regimen exists. Development of such a regimen is thus an urgent issue.
Antigen-specific CTL therapy can induce durable remission in selected tumors such as melanomas.7-10 ENKL cells are invariably infected by Epstein-Barr virus (EBV) with type II latency; they express the EBV antigens latent membrane protein (LMP) 1 and LMP2 (LMP1/2). As T cells specific for these antigens are infrequent and often are anergic in the tumor microenvironment, ENKL should be a good tar- get for CTL therapy directed against LMP1 and LMP2.11-16 However, CTL continu- ously exposed to viral or tumor antigens become exhausted.17
Exploiting fully rejuvenated CTL innovatively overcomes CTL exhaustion. We generated antigen-specific CTL directed against LMP1 and LMP2 from iPSC estab- lished from peripheral blood-derived antigen-specific CTL.18-20 The iPSC-derived CTL have the same antigen specificity as the original CTL. As these redifferentiat- ed CTL have a higher proliferative capacity, younger memory phenotype, and
*HN and NK are co-last authors
Correspondence:
MIKI ANDO
m-ando@juntendo.ac.jp
HIROMITSU NAKAUCHI
nakauchi@stanford.edu
Received: April 2, 2019. Accepted: July 10, 2019. Pre-published: July 11, 2019.
doi:10.3324/haematol.2019.223511
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/796
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