Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination

Yasushi Akahori, Linan Wang, Motohiro Yoneyama, Naohiro Seo, Satoshi Okumura, Yoshihiro Miyahara, Yasunori Amaishi, Sachiko Okamoto, Junichi Mineno, Hiroaki Ikeda, Takehiro Maki, Hiroshi Fujiwara, Yoshiki Akatsuka, Takuma Kato, Hiroshi Shiku

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The recent success of chimeric antigen receptor (CAR)-T cell therapy for treatment of hematologic malignancies supports further development of treatments for both liquid and solid tumors. However, expansion of CAR-T cell therapy is limited by the availability of surface antigens specific for the tumor while sparing normal cells. There is a rich diversity of tumor antigens from intracellularly expressed proteins that current and conventional CAR-T cells are unable to target. Furthermore, adoptively transferred T cells often suffer from exhaustion and insufficient expansion, in part, because of the immunosuppressive mechanisms operating in tumor-bearing hosts. Therefore, it is necessary to develop means to further activate and expand those CAR-T cells in vivo. The Wilms tumor 1 (WT1) is an intracellular oncogenic transcription factor that is an attractive target for cancer immunotherapy because of its overexpression in a wide range of leukemias and solid tumors, and a low level of expression in normal adult tissues. In the present study, we developed CART cells consisting of a single chain variable fragment (scFv) specific to the WT1235-243/HLA-A*2402 complex. The therapeutic efficacy of our CAR-T cells was demonstrated in a complex can be boosted by vaccination.

Original languageEnglish
Pages (from-to)1134-1145
Number of pages12
JournalBlood
Volume132
Issue number11
DOIs
Publication statusPublished - 13-09-2018

Fingerprint

Wilms Tumor
Oncogene Proteins
T-Cell Antigen Receptor
Tumors
Vaccination
Antigen Receptors
Neoplasms
Cell- and Tissue-Based Therapy
Bearings (structural)
Single-Chain Antibodies
HLA-A Antigens
T-cells
Neoplasm Antigens
Hematologic Neoplasms
Surface Antigens
Immunosuppressive Agents
Immunotherapy
Leukemia
Transcription Factors
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Akahori, Y., Wang, L., Yoneyama, M., Seo, N., Okumura, S., Miyahara, Y., ... Shiku, H. (2018). Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination. Blood, 132(11), 1134-1145. https://doi.org/10.1182/blood-2017-08-802926
Akahori, Yasushi ; Wang, Linan ; Yoneyama, Motohiro ; Seo, Naohiro ; Okumura, Satoshi ; Miyahara, Yoshihiro ; Amaishi, Yasunori ; Okamoto, Sachiko ; Mineno, Junichi ; Ikeda, Hiroaki ; Maki, Takehiro ; Fujiwara, Hiroshi ; Akatsuka, Yoshiki ; Kato, Takuma ; Shiku, Hiroshi. / Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination. In: Blood. 2018 ; Vol. 132, No. 11. pp. 1134-1145.
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abstract = "The recent success of chimeric antigen receptor (CAR)-T cell therapy for treatment of hematologic malignancies supports further development of treatments for both liquid and solid tumors. However, expansion of CAR-T cell therapy is limited by the availability of surface antigens specific for the tumor while sparing normal cells. There is a rich diversity of tumor antigens from intracellularly expressed proteins that current and conventional CAR-T cells are unable to target. Furthermore, adoptively transferred T cells often suffer from exhaustion and insufficient expansion, in part, because of the immunosuppressive mechanisms operating in tumor-bearing hosts. Therefore, it is necessary to develop means to further activate and expand those CAR-T cells in vivo. The Wilms tumor 1 (WT1) is an intracellular oncogenic transcription factor that is an attractive target for cancer immunotherapy because of its overexpression in a wide range of leukemias and solid tumors, and a low level of expression in normal adult tissues. In the present study, we developed CART cells consisting of a single chain variable fragment (scFv) specific to the WT1235-243/HLA-A*2402 complex. The therapeutic efficacy of our CAR-T cells was demonstrated in a complex can be boosted by vaccination.",
author = "Yasushi Akahori and Linan Wang and Motohiro Yoneyama and Naohiro Seo and Satoshi Okumura and Yoshihiro Miyahara and Yasunori Amaishi and Sachiko Okamoto and Junichi Mineno and Hiroaki Ikeda and Takehiro Maki and Hiroshi Fujiwara and Yoshiki Akatsuka and Takuma Kato and Hiroshi Shiku",
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Akahori, Y, Wang, L, Yoneyama, M, Seo, N, Okumura, S, Miyahara, Y, Amaishi, Y, Okamoto, S, Mineno, J, Ikeda, H, Maki, T, Fujiwara, H, Akatsuka, Y, Kato, T & Shiku, H 2018, 'Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination', Blood, vol. 132, no. 11, pp. 1134-1145. https://doi.org/10.1182/blood-2017-08-802926

Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination. / Akahori, Yasushi; Wang, Linan; Yoneyama, Motohiro; Seo, Naohiro; Okumura, Satoshi; Miyahara, Yoshihiro; Amaishi, Yasunori; Okamoto, Sachiko; Mineno, Junichi; Ikeda, Hiroaki; Maki, Takehiro; Fujiwara, Hiroshi; Akatsuka, Yoshiki; Kato, Takuma; Shiku, Hiroshi.

In: Blood, Vol. 132, No. 11, 13.09.2018, p. 1134-1145.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination

AU - Akahori, Yasushi

AU - Wang, Linan

AU - Yoneyama, Motohiro

AU - Seo, Naohiro

AU - Okumura, Satoshi

AU - Miyahara, Yoshihiro

AU - Amaishi, Yasunori

AU - Okamoto, Sachiko

AU - Mineno, Junichi

AU - Ikeda, Hiroaki

AU - Maki, Takehiro

AU - Fujiwara, Hiroshi

AU - Akatsuka, Yoshiki

AU - Kato, Takuma

AU - Shiku, Hiroshi

PY - 2018/9/13

Y1 - 2018/9/13

N2 - The recent success of chimeric antigen receptor (CAR)-T cell therapy for treatment of hematologic malignancies supports further development of treatments for both liquid and solid tumors. However, expansion of CAR-T cell therapy is limited by the availability of surface antigens specific for the tumor while sparing normal cells. There is a rich diversity of tumor antigens from intracellularly expressed proteins that current and conventional CAR-T cells are unable to target. Furthermore, adoptively transferred T cells often suffer from exhaustion and insufficient expansion, in part, because of the immunosuppressive mechanisms operating in tumor-bearing hosts. Therefore, it is necessary to develop means to further activate and expand those CAR-T cells in vivo. The Wilms tumor 1 (WT1) is an intracellular oncogenic transcription factor that is an attractive target for cancer immunotherapy because of its overexpression in a wide range of leukemias and solid tumors, and a low level of expression in normal adult tissues. In the present study, we developed CART cells consisting of a single chain variable fragment (scFv) specific to the WT1235-243/HLA-A*2402 complex. The therapeutic efficacy of our CAR-T cells was demonstrated in a complex can be boosted by vaccination.

AB - The recent success of chimeric antigen receptor (CAR)-T cell therapy for treatment of hematologic malignancies supports further development of treatments for both liquid and solid tumors. However, expansion of CAR-T cell therapy is limited by the availability of surface antigens specific for the tumor while sparing normal cells. There is a rich diversity of tumor antigens from intracellularly expressed proteins that current and conventional CAR-T cells are unable to target. Furthermore, adoptively transferred T cells often suffer from exhaustion and insufficient expansion, in part, because of the immunosuppressive mechanisms operating in tumor-bearing hosts. Therefore, it is necessary to develop means to further activate and expand those CAR-T cells in vivo. The Wilms tumor 1 (WT1) is an intracellular oncogenic transcription factor that is an attractive target for cancer immunotherapy because of its overexpression in a wide range of leukemias and solid tumors, and a low level of expression in normal adult tissues. In the present study, we developed CART cells consisting of a single chain variable fragment (scFv) specific to the WT1235-243/HLA-A*2402 complex. The therapeutic efficacy of our CAR-T cells was demonstrated in a complex can be boosted by vaccination.

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