Induction of anti-leukemia immunity in humanized mice by allogeneic human iPSC-derived iNKT cells bearing a CD19-CAR: Adjuvant activity of CAR iPSC-iNKT cells

Aoki, Takahiro; Yun-Hsuan  Chang; Yui  Iijima; Midori  Kobayashi; Momokoi  Okosh; Munechika  Yamaguchi; Hiroko  Okura; Satoko  Sasaki; Sachiko  Kira; Yoshie  Sasako; Nayuta  Yakushiji-Kaminatsui; Jafar  Sharif; Masashi  Matsuda; Kiwamu  Motoyoshi; Katsuhiro  Nishimura; Ko  Ozaki; Daiki  Shimizu; Hongxuan  Wang; Mariko Takami; Moeko Hino; Atsushi  Onodera; Kiyoshi  Hirahara; Motoko  Y. Kimura; Ari Itoh-Nakadai; Fumihiko  Ishikawa; Manabu  Nakayama; Shinichiro Motohashi; Haruhiko  Koseki

doi:10.51094/jxiv.3886

##article.authors##

Aoki, Takahiro Chiba University
Yun-Hsuan Chang RIKEN Center for Integrative Medical Sciences
Yui Iijima Graduate School of Medicine, Chiba University
Midori Kobayashi Graduate School of Medicine, Chiba University
Momokoi Okosh RIKEN Center for Integrative Medical Sciences
Munechika Yamaguchi RIKEN Center for Integrative Medical Sciences
Hiroko Okura RIKEN Center for Integrative Medical Sciences
Satoko Sasaki RIKEN Center for Integrative Medical Sciences
Sachiko Kira RIKEN Center for Integrative Medical Sciences
Yoshie Sasako RIKEN Center for Integrative Medical Sciences
Nayuta Yakushiji-Kaminatsui RIKEN Center for Integrative Medical Sciences
Jafar Sharif RIKEN Center for Integrative Medical Sciences
Masashi Matsuda RIKEN Center for Integrative Medical Sciences
Kiwamu Motoyoshi RIKEN Center for Integrative Medical Sciences
Katsuhiro Nishimura Graduate School of Medicine, Chiba University
Ko Ozaki Graduate School of Medicine, Chiba University
Daiki Shimizu Graduate School of Medicine, Chiba University
Hongxuan Wang Graduate School of Medicine, Chiba University
Mariko Takami Graduate School of Medicine, Chiba University
Moeko Hino Graduate School of Medicine, Chiba University
Atsushi Onodera Graduate School of Medicine, Chiba University
Kiyoshi Hirahara Graduate School of Medicine, Chiba University
Motoko Y. Kimura Graduate School of Medicine, Chiba University
Ari Itoh-Nakadai RIKEN Center for Integrative Medical Sciences
Fumihiko Ishikawa RIKEN Center for Integrative Medical Sciences
Manabu Nakayama Kazusa DNA Research Institute
Shinichiro Motohashi Graduate School of Medicine, Chiba University
Haruhiko Koseki RIKEN Center for Integrative Medical Science

DOI:

https://doi.org/10.51094/jxiv.3886

キーワード:

allogeneic iPS cells,、 invariant NKT cells,、 chimeric antigen receptors,、 adaptive T-cell immunity,、 CD19-independent cytotoxicity

抄録

CD19-chimeric antigen receptor (CAR) T-cell therapy demonstrates remarkable efficacy against B-cell malignancies; however, this efficacy is reduced by several factors, including antigen loss and limited CAR T-cell persistence. Invariant natural killer T (iNKT) cells possess adjuvant activity that enhances long-term adaptive immunity and have been shown to function as a CD19-CAR platform in a mouse leukemia therapy model. Allogeneic human iNKT cells derived from induced pluripotent stem cells (iPSC-iNKT cells) exerted some, albeit limited, clinical efficacy. We therefore expected that CAR and iPSC-iNKT-cell technologies could complement each other’s limitations to enhance anti-cancer effectiveness. We thus generated human iPSC-iNKT cells bearing a CD19-CAR (CD19-CAR iPSC-iNKT cells) and performed preclinical studies in humanized mice harboring human peripheral blood mononuclear cells (PBMCs). We first established a human leukemia therapy model in immunodeficient mice, in which CD19⁺ leukemia cells were depleted by serially introducing human PBMCs and allogeneic CD19-CAR iPSC-iNKT cells. Mechanistically, CD19-CAR iPSC-iNKT cells, activated by recognizing CD19 on leukemia cells, damage the leukemia cells and promote their phagocytosis and maturation of dendritic cells (DCs), and thus facilitate the induction of leukemia-reactive memory-T cells. The induced T cells appear to recognize leukemia-derived antigens but not CD19 or any other normal B-cell antigens. Therefore, allogeneic CD19-CAR iPSC-iNKT cells exert anti-cancer effects via mechanisms different from CD19-CAR T cells and, thereby, may be complementary to CD19-CAR T-cell therapy and may also be an attractive platform for other CARs to generate cancer-directed T-cell immunity.

利益相反に関する開示

H. Koseki and S. Motohashi received grants from BrightPath Biotherapeutics Co., Ltd., T.T. Aoki, YH. Chang, M., Kobayashi, K., Nishimura, S., Motohashi, F., Ishikawa, and H. Koseki have a patent application related to this work.

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引用文献

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Induction of anti-leukemia immunity in humanized mice by allogeneic human iPSC-derived iNKT cells bearing a CD19-CAR

Adjuvant activity of CAR iPSC-iNKT cells