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7. Cellular and Humoral Immune Responses Induced by an HLA Class I–restricted Peptide Cancer Vaccine Targeting WT1 Are Associated With Favorable Clinical Outcomes in Advanced Ovarian Cancer

Author

Nishida, Sumiyuki, Morimoto, Soyoko, Oji, Yusuke, Morita, Satoshi, Shirakata, Toshiaki, Enomoto, Takayuki, Tsuboi, Akihiro, Ueda, Yutaka, Yoshino, Kiyoshi, Shouq, Alzaaqi, Kanegae, Mizuki, Ohno, Satoshi, Fujiki, Fumihiro, Nakajima, Hiroko, Nakae, Yoshiki, Nakata, Jun, Hosen, Naoki, Kumanogoh, Atsushi, Oka, Yoshihiro, Kimura, Tadashi, and Sugiyama, Haruo

Published
2022
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9. Induction of WT1 (Wilms' Tumor Gene)-Specific Cytotoxic T Lymphocytes by WT1 Peptide Vaccine and the Resultant Cancer Regression

Author

Oka, Yoshihiro, Tsuboi, Akihiro, Taguchi, Tetsuya, Osaki, Tadashi, Kyo, Taiichi, Nakajima, Hiroko, Elisseeva, Olga A., Oji, Yusuke, Kawakami, Manabu, Ikegame, Kazuhiro, Hosen, Naoki, Yoshihara, Satoshi, Wu, Fei, Fujiki, Fumihiro, Murakami, Masaki, Masuda, Tomoki, Nishida, Sumiyuki, Shirakata, Toshiaki, Nakatsuka, Shin-ichi, Sasaki, Ayako, Udaka, Keiko, Dohy, Hiroo, Aozasa, Katsuyuki, Noguchi, Shinzaburo, Kawase, Ichiro, Sugiyama, Haruo, and Sugimura, Takashi

Published
2004

10. The activated conformation of integrin [beta]7 is a novel multiple myeloma-specific target for CAR T cell therapy

Author

Hosen, Naoki, Matsunaga, Yukiko, Hasegawa, Kana, Matsuno, Hiroshi, Nakamura, Yuki, Makita, Mio, Watanabe, Kouki, Yoshida, Mikako, Satoh, Kei, Morimoto, Soyoko, Fujiki, Fumihiro, Nakajima, Hiroko, Nakata, Jun, Nishida, Sumiyuki, Tsuboi, Akihiro, Oka, Yoshihiro, Manabe, Masahiro, Ichihara, Hiroyoshi, Aoyama, Yasutaka, Mugitani, Atsuko, Nakao, Takafumi, Hino, Masayuki, Uchibori, Ryosuke, Ozawa, Keiya, Baba, Yoshihiro, Terakura, Seitaro, Wada, Naoki, Morii, Eiichi, Nishimura, Junichi, Takeda, Kiyoshi, Oji, Yusuke, Sugiyama, Haruo, Takagi, Junichi, and Kumanogoh, Atsushi

Subjects
Immunotherapy -- Health aspects -- Genetic aspects -- Research, Multiple myeloma -- Genetic aspects -- Care and treatment -- Research, Integrins -- Physiological aspects -- Structure -- Genetic aspects -- Research, T cells -- Health aspects -- Physiological aspects -- Genetic aspects -- Research, Biological sciences, Health
Abstract

Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened [greater than] 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin [beta][sub.7] molecules. The MMG49 epitope, in the N-terminal region of the [beta][sub.7] chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin [beta][sub.7] conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin [beta][sub.7][sup.+] lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target., Author(s): Naoki Hosen (corresponding author) [1, 2, 3]; Yukiko Matsunaga [4]; Kana Hasegawa [1]; Hiroshi Matsuno [5]; Yuki Nakamura [1]; Mio Makita [1]; Kouki Watanabe [1]; Mikako Yoshida [1]; Kei [...]

Published
2017
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12. Wilms tumor 1 peptide vaccination combined with temozolomide against newly diagnosed glioblastoma: safety and impact on immunological response

Author

Hashimoto, Naoya, Tsuboi, Akihiro, Kagawa, Naoki, Chiba, Yasuyoshi, Izumoto, Shuichi, Kinoshita, Manabu, Kijima, Noriyuki, Oka, Yoshihiro, Morimoto, Soyoko, Nakajima, Hiroko, Morita, Satoshi, Sakamoto, Junichi, Nishida, Sumiyuki, Hosen, Naoki, Oji, Yusuke, Arita, Norio, Yoshimine, Toshiki, and Sugiyama, Haruo

Published
2015
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13. WT1 Trio Peptide-Based Cancer Vaccine for Rare Cancers Expressing Shared Target WT1.

Author

Oji, Yusuke, Kagawa, Naoki, Arita, Hideyuki, Naka, Norifumi, Hamada, Ken-ichiro, Outani, Hidetatsu, Shintani, Yasushi, Takeda, Yoshito, Morii, Eiichi, Shimazu, Kenzo, Suzuki, Motoyuki, Nishida, Sumiyuki, Nakata, Jun, Tsuboi, Akihiro, Iwai, Miki, Hayashi, Sae, Imanishi, Rin, Ikejima, Sayaka, Kanegae, Mizuki, and Iwamoto, Masahiro

Subjects
TUMOR prevention, PROTEINS, CLINICAL trials, IMMUNOGLOBULINS, MYASTHENIA gravis, PEPTIDE vaccines, VACCINE effectiveness, GENE expression, RESEARCH funding, CANCER vaccines, T cells, DRUG allergy, RARE diseases, IMMUNOTHERAPY, EVALUATION
Abstract

Simple Summary: Therapeutic options for rare cancers are frequently limited and less effective than for common cancers. Therefore, novel therapeutic strategies to treat rare cancers are urgently required. Our clinical study on rare cancers showed that the biweekly WT1 Trio peptide vaccine comprising two WT1-cytotoxic T lymphocyte (CTL)-peptides and one WT1-helper T lymphocyte-peptide induced more robust immune responses targeting WT1 than the weekly WT1-CTL peptide (WT1-235) vaccine. In addition, the safety of WT1 Trio was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer (TC). Fifteen (33.3%) of the 45 patients with recurrent or advanced rare cancers, including malignant glioma, soft-tissue sarcoma, TC, and malignant pleural mesothelioma, achieved stable disease after 3 months of protocol treatment. Therefore, since WT1 is widely overexpressed in rare cancers, WT1-targeted immunotherapy may be a therapeutic strategy for rare cancers. No standard treatment has been established for most rare cancers. Here, we report a clinical trial of a biweekly WT1 tri-peptide-based vaccine for recurrent or advanced rare cancers. Due to the insufficient number of patients available for a traditional clinical trial, the trial was designed for rare cancers expressing shared target molecule WT1. The recruitment criteria included WT1-expressing tumors as well as HLA-A*24:02 or 02:01. The primary endpoints were immunoglobulin G (IgG) antibody (Ab) production against the WT1-235 cytotoxic T lymphocyte (CTL) epitope and delayed-type hypersensitivity (DTH) skin reactions to targeted WT1 CTL epitopes. The secondary endpoints were safety and clinical efficacy. Forty-five patients received WT1 Trio, and 25 (55.6%) completed the 3-month protocol treatment. WT1-235 IgG Ab was positive in 88.0% of patients treated with WT1 Trio at 3 months, significantly higher than 62.5% of the weekly WT1-235 CTL peptide vaccine. The DTH positivity rate in WT1 Trio was 62.9%, which was not significantly different from 60.7% in the WT1-235 CTL peptide vaccine. The WT1 Trio safety was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer. Fifteen (33.3%) patients achieved stable disease after 3 months of treatment. In conclusion, the biweekly WT1 Trio vaccine containing the WT1-332 helper T lymphocyte peptide induced more robust immune responses targeting WT1 than the weekly WT1-235 CTL peptide vaccine. Therefore, WT1-targeted immunotherapy may be a potential therapeutic strategy for rare cancers. [ABSTRACT FROM AUTHOR]

Published
2023
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19. T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy.

Author

Fujiki, Fumihiro, Morimoto, Soyoko, Katsuhara, Akiko, Okuda, Akane, Ogawa, Saeka, Ueda, Eriko, Miyazaki, Maki, Isotani, Ayako, Ikawa, Masahito, Nishida, Sumiyuki, Nakajima, Hiroko, Tsuboi, Akihiro, Oka, Yoshihiro, Nakata, Jun, Hosen, Naoki, Kumanogoh, Atsushi, Oji, Yusuke, and Sugiyama, Haruo

Subjects
T cell differentiation, RETINOIC acid receptors, VITAMIN A, IMMUNOMODULATORS, VITAMINS
Abstract

Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Published
2022
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20. Wilms Tumor gene WT1 peptide-based immunotherapy induced a minimal response in a patient with advanced therapy-resistant multiple myeloma

Author

Tsuboi, Akihiro, Oka, Yoshihiro, Nakajima, Hiroko, Fukuda, Yoko, Elisseeva, Olga A., Yoshihara, Satoshi, Hosen, Naoki, Ogata, Atsushi, Kito, Katsuyuki, Fujiki, Fumihiro, Nishida, Sumiyuki, Shirakata, Toshiaki, Ohno, Satoshi, Yasukawa, Masaki, Oji, Yusuke, Kawakami, Manabu, Morita, Satoshi, Sakamoto, Junichi, Udaka, Keiko, Kawase, Ichiro, and Sugiyama, Haruo

Published
2007
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22. WT1 peptide vaccination combined with BCG-CWS is more efficient for tumor eradication than WT1 peptide vaccination alone

Author

Nakajima, Hiroko, Kawasaki, Kotomi, Oka, Yoshihiro, Tsuboi, Akihiro, Kawakami, Manabu, Ikegame, Kazuhiro, Hoshida, Yoshihiko, Fujiki, Fumihiro, Nakano, Akiko, Masuda, Tomoki, Wu, Fei, Taniguchi, Yuki, Yoshihara, Satoshi, Elisseeva, Olga A., Oji, Yusuke, Ogawa, Hiroyasu, Azuma, Ichiro, Kawase, Ichiro, Aozasa, Katsuyuki, and Sugiyama, Haruo

Published
2004
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23. Monitoring Minimal Residual Disease in Leukemia Using Real-time Quantitative Polymerase Chain Reaction for Wilms Tumor Gene (WT1)

Author

Tamaki, Hiroya, Mishima, Machiko, Kawakami, Manabu, Tsuboi, Akihiro, Kim, Eui Ho, Hosen, Naoki, Ikegame, Kazuhiro, Murakami, Masaki, Fujioka, Tatsuya, Masuda, Tomoki, Taniguchi, Yuki, Nishida, Sumiyuki, Osumi, Kazuoki, Soma, Toshihiro, Oji, Yusuke, Oka, Yoshihiro, Kawase, Ichiro, Sugiyama, Haruo, and Ogawa, Hiroyasu

Published
2003
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24. The lck Promoter-Driven Expression of the Wilms Tumor Gene WT1 Blocks Intrathymic Differentiation of T-Lineage Cells

Author

Li, Hanfen, Oka, Yoshihiro, Tsuboi, Akihiro, Yamagami, Tamotsu, Miyazaki, Toru, Yusa, Sei-ichi, Kawasaki, Kotomi, Kishimoto, Yukiko, Asada, Momotaro, Nakajima, Hiroko, Kanato, Keisuke, Nishida, Sumiyuki, Masuda, Tomoki, Murakami, Masaki, Hosen, Naoki, Kawakami, Manabu, Ogawa, Hiroyasu, Melchers, Fritz, Kawase, Ichiro, Oji, Yusuke, and Sugiyama, Haruo

Published
2003
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26. Enhanced induction of human WT1-specific cytotoxic T lymphocytes with a 9-mer WT1 peptide modified at HLA-A*2402-binding residues

Author

Tsuboi, Akihiro, Oka, Yoshihiro, Udaka, Keiko, Murakami, Masaki, Masuda, Tomoki, Nakano, Akiko, Nakajima, Hiroko, Yasukawa, Masaki, Hiraki, Akio, Oji, Yusuke, Kawakami, Manabu, Hosen, Naoki, Fujioka, Tatsuya, Wu, Fei, Taniguchi, Yuki, Nishida, Sumiyuki, Asada, Momotaro, Ogawa, Hiroyasu, Kawase, Ichiro, and Sugiyama, Haruo

Published
2002
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28. Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain.

Author

Hasegawa, Kana, Ikeda, Shunya, Yaga, Moto, Watanabe, Kouki, Urakawa, Rika, Iehara, Akie, Iwai, Mai, Hashiguchi, Seishin, Morimoto, Soyoko, Fujiki, Fumihiro, Nakajima, Hiroko, Nakata, Jun, Nishida, Sumiyuki, Tsuboi, Akihiro, Oka, Yoshihiro, Yoshihara, Satoshi, Manabe, Masahiro, Ichihara, Hiroyoshi, Mugitani, Atsuko, and Aoyama, Yasutaka

Subjects
MULTIPLE myeloma, CELL surface antigens, PROTEOMICS, MONOCLONAL antibodies, PROTEINS, HEMATOLOGIC malignancies
Abstract

Cancer-specific cell surface antigens are ideal therapeutic targets for monoclonal antibody (mAb)–based therapy. Here, we report that multiple myeloma (MM), an incurable hematological malignancy, can be specifically targeted by an mAb that recognizes a ubiquitously present protein, CD98 heavy chain (hc) (also known as SLC3A2). We screened more than 10,000 mAb clones raised against MM cells and identified R8H283, an mAb that bound MM cells but not normal hematopoietic or nonhematopoietic cells. R8H283 specifically recognized CD98hc. R8H283 did not react with monomers of CD98hc; instead, it bound CD98hc in heterodimers with a CD98 light chain (CD98lc), a complex that functions as an amino acid transporter. CD98 heterodimers were abundant on MM cells and took up amino acids for constitutive production of immunoglobulin. Although CD98 heterodimers were also present on normal leukocytes, R8H283 did not react with them. The glycoforms of CD98hc present on normal leukocytes were distinct from those present on MM cells, which may explain the lack of R8H283 reactivity to normal leukocytes. R8H283 exerted anti-MM effects without damaging normal hematopoietic cells. These findings suggested that R8H283 is a candidate for mAb-based therapies for MM. In addition, our findings showed that a cancer-specific conformational epitope in a ubiquitous protein, which cannot be identified by transcriptome or proteome analyses, can be found by extensive screening of primary human tumor samples. A myeloma-targeting mAb: Searching for cancer-specific surface antigens could identify potential targets for cancer therapy that may be missed by -omic approaches. Here, Hasegawa and colleagues screened monoclonal antibody (mAb) clones against patient-derived multiple myeloma (MM) cells, in the process identifying R8H283, an mAb that recognized the CD98 heavy chain protein, which is part of an amino acid transporter. Despite the ubiquitous presence of CD98 heavy chain in normal cells, the mAb only bound to MM cells, and differing glycosylation patterns between normal cells and MM cells contributed to this selectivity. In MM xenograft models in mice, R8H283 injections prolonged survival, suggesting that the mAb should be further assessed for utility in treating MM. [ABSTRACT FROM AUTHOR]

Published
2022
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30. Biased usage of T cell receptor β-chain variable region genes of Wilmsʼ tumor gene (WT1)-specific CD8+ T cells in patients with solid tumors and healthy donors

Author

Morimoto, Soyoko, Oka, Yoshihiro, Tsuboi, Akihiro, Tanaka, Yukie, Fujiki, Fumihiro, Nakajima, Hiroko, Hosen, Naoki, Nishida, Sumiyuki, Nakata, Jun, Nakae, Yoshiki, Maruno, Motohiko, Myoui, Akira, Enomoto, Takayuki, Izumoto, Shuichi, Sekimoto, Mitsugu, Kagawa, Naoki, Hashimoto, Naoya, Yoshimine, Toshiki, Oji, Yusuke, Kumanogoh, Atsushi, and Sugiyama, Haruo

Published
2012
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31. CD48 as a novel molecular target for antibody therapy in multiple myeloma

Author

Hosen, Naoki, Ichihara, Hiroyoshi, Mugitani, Atsuko, Aoyama, Yasutaka, Fukuda, Yuki, Kishida, Satoshi, Matsuoka, Yoshikazu, Nakajima, Hiroko, Kawakami, Manabu, Yamagami, Tamotsu, Fuji, Shigeo, Tamaki, Hiroya, Nakao, Takafumi, Nishida, Sumiyuki, Tsuboi, Akihiro, Iida, Shinsuke, Hino, Masayuki, Oka, Yoshihiro, Oji, Yusuke, and Sugiyama, Haruo

Published
2012
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35. High frequencies of less differentiated and more proliferative WT1-specific CD8+ T cells in bone marrow in tumor-bearing patients: An important role of bone marrow as a secondary lymphoid organ

Author

Murao, Ayako, Oka, Yoshihiro, Tsuboi, Akihiro, Elisseeva, Olga A., Tanaka-Harada, Yukie, Fujiki, Fumihiro, Nakajima, Hiroko, Nishida, Sumiyuki, Hosen, Naoki, Shirakata, Toshiaki, Hashimoto, Nobuyuki, Myoui, Akira, Ueda, Takafumi, Takeda, Yoshito, Osaki, Tadashi, Enomoto, Takayuki, Yoshikawa, Hideki, Kimura, Tadashi, Oji, Yusuke, Kawase, Ichiro, and Sugiyama, Haruo

Published
2010
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37. WT1 IgG antibody for early detection of nonsmall cell lung cancer and as its prognostic factor

Author

Oji, Yusuke, Kitamura, Yayoi, Kamino, Eriko, Kitano, Aiko, Sawabata, Noriyoshi, Inoue, Masayoshi, Mori, Masahide, Nakatsuka, Shin-ichi, Sakaguchi, Nao, Miyazaki, Kaori, Nakamura, Michiyo, Fukuda, Ikuyo, Nakamura, Junya, Tatsumi, Naoya, Takakuwa, Tetsuya, Nishida, Sumiyuki, Shirakata, Toshiaki, Hosen, Naoki, Tsuboi, Akihiro, Nezu, Riichiro, Maeda, Hajime, Oka, Yoshihiro, Kawase, Ichiro, Aozasa, Katsuyuki, Okumura, Meinoshin, Miyoshi, Shinichiro, and Sugiyama, Haruo

Published
2009
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38. Identification of mouse helper epitopes for WT1-specific CD4+ T cells.

Author

Nakajima, Hiroko, Nakata, Jun, Imafuku, Kanako, Hayashibara, Hiromu, Isokawa, Kazuki, Udaka, Keiko, Fujiki, Fumihiro, Morimoto, Soyoko, Hasegawa, Kana, Hosen, Naoki, Hashii, Yoshiko, Nishida, Sumiyuki, Tsuboi, Akihiro, Oka, Yoshihiro, Oji, Yusuke, Sogo, Shinji, and Sugiyama, Haruo

Subjects
T cells, CYTOTOXIC T cells, LABORATORY mice, EPITOPES, MICE, REJECTION (Psychology)
Abstract

Helper T lymphocytes (HTLs) play a central role in cancer immunity because they can not only help the induction and proliferation of cytotoxic T lymphocytes (CTLs) but also their differentiation into cytotoxic CD4+ T cells and directly kill the target cells.This study describes the identification of three novel mouse Th epitope peptides, WT135-52, WT186-102 and WT1294-312, derived from WT1 protein, which is the most potent tumor-associated antigen. Compared to immunization with WT1 CTL peptide alone, immunization with the addition of these WT1-specific Th peptides strongly induced WT1-specific CTLs, continued to maintain them, and efficiently rejected the challenge of WT1-expressing tumor cells. Importantly, the majority of WT1-specific CTLs induced by the co-immunization with WT1 CTL and the WT1-specific Th peptides were CD44+CD62L− effector memory CD8+ T cells, which played a central role in tumor rejection. Establishment of mouse models suitable for the analysis of the detailed mechanism of these functions of HTLs is very important. These results clearly showed that WT1-specific HTLs perform an essential function in WT1-specific tumor immunity. Therefore, the WT1-specific Th peptides identified here should make a major contribution to elucidation of the mutual roles of WT1-specific CTLs and HTLs in cancer immunity in in vivo mouse models. [ABSTRACT FROM AUTHOR]

Published
2021
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42. A Phase I/II Trial of a WT1 (Wilmsʼ Tumor Gene) Peptide Vaccine in Patients with Solid Malignancy: Safety Assessment Based on the Phase I Data

Author

Morita, Satoshi, Oka, Yoshihiro, Tsuboi, Akihiro, Kawakami, Manabu, Maruno, Motohiko, Izumoto, Shuichi, Osaki, Tadashi, Taguchi, Tetsuya, Ueda, Takafumi, Myoui, Akira, Nishida, Sumiyuki, Shirakata, Toshiaki, Ohno, Satoshi, Oji, Yusuke, Aozasa, Katsuyuki, Hatazawa, Jun, Udaka, Keiko, Yoshikawa, Hideki, Yoshimine, Toshiki, Noguchi, Shinzaburo, Kawase, Ichiro, Nakatsuka, Shin-ichi, Sugiyama, Haruo, and Sakamoto, Junichi

Published
2006

44. Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells

Author

Hosen, Naoki, Sonoda, Yoshiaki, Oji, Yusuke, Kimura, Takafumi, Minamiguchi, Hitoshi, Tamaki, Hiroya, Kawakami, Manabu, Asada, Momotaro, Kanato, Keisuke, Motomura, Mari, Murakami, Masaki, Fujioka, Tatsuya, Masuda, Tomoki, Kim, Eui Ho, Tsuboi, Akihiro, Oka, Yoshihiro, Soma, Toshihiro, Ogawa, Hiroyasu, and Sugiyama, Haruo

Published
2002

47. Humoral immune responses against Wilms tumor gene WT1product in patients with hematopoietic malignancies

Author

Elisseeva, Olga A., Oka, Yoshihiro, Tsuboi, Akihiro, Ogata, Kiyoyuki, Wu, Fei, Kim, Eui Ho, Soma, Toshihiro, Tamaki, Hiroya, Kawakami, Manabu, Oji, Yusuke, Hosen, Naoki, Kubota, Takeshi, Nakagawa, Masashi, Yamagami, Tamotsu, Hiraoka, Akira, Tsukaguchi, Machiko, Udaka, Keiko, Ogawa, Hiroyasu, Kishimoto, Tadamitsu, Nomura, Taisei, and Sugiyama, Haruo

Published
2002
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48. Encouraging Clinical Evolution of a Pediatric Patient With Relapsed Diffuse Midline Glioma Who Underwent WT1-Targeting Immunotherapy: A Case Report and Literature Review.

Author

Hashii, Yoshiko, Oka, Yoshihiro, Kagawa, Naoki, Hashimoto, Naoya, Saitou, Hiroyuki, Fukuya, Syogo, Kanegae, Mizuki, Ikejima, Sayaka, Oji, Yusuke, Ozono, Keiichi, Tsuboi, Akihiro, and Sugiyama, Haruo

Subjects
CYTOTOXIC T cells, OLIGODENDROGLIOMAS, GLIOMAS, IMMUNOTHERAPY, LITERATURE reviews, NEPHROBLASTOMA
Abstract

Diffuse midline glioma (DMG) in children is a highly aggressive, malignant brain tumor that is fatal when relapsed. Wilms tumor 1 (WT1) is a high-priority antigen target for cancer immunotherapy. We hereby report on a pediatric patient who had DMG that regrew after chemoradiotherapy and underwent WT1 peptide vaccination. A 13-year-old Japanese boy presented with vertigo, diplopia, and right hemiplegia at the initial visit to another hospital, where he was diagnosed with DMG by magnetic resonance imaging (MRI); DMG was categorized to histological grade IV glioma. The patient underwent radiotherapy and chemotherapy with temozolomide. After three cycles of chemotherapy, MRI revealed tumor regrowth that translated into deteriorated clinical manifestations. Immunohistochemically, the H3.3K27M mutation in the biopsy specimen was confirmed and the specimen was positive for WT1 protein. The patient underwent WT1-targeting immunotherapy with the WT1-specific peptide vaccine because of having HLA-A*24:02. Consequently, his quality of life drastically improved so much as to the extent that the patient became capable of conducting nearly normal daily activities at weeks 8 to 12 of vaccination. MRI at week 8 of vaccination revealed an obvious reduction in the signal intensity of the tumor. Furthermore, betamethasone dose could be reduced successively (4, 1, and 0.5 mg/day at weeks 4, 5, and 7, respectively) without deteriorating clinical manifestations. Best response among responses assessed according to the Response Assessment in Neuro-Oncology criteria was stable disease. Overall survival was 6.5 months after vaccination onset and was 8.3 months after relapse; the latter was markedly longer than the reported median OS of 3.2 months for pediatric patients with relapsed DMG in the literature. Modified WT1 tetramer staining revealed the WT1 peptide vaccine-induced production of WT1-specific cytotoxic T cells, and the interferon-γ (IFN-γ) ELISpot assay of peripheral blood mononuclear cells disclosed the production of IFN-γ. Delayed-type hypersensitivity test became positive. Any treatment-emergent adverse events did not occur except injection site erythema. Our pediatric patient exhibited an encouraging clinical evolution as manifested by stable disease, improved clinical manifestations, steroid dose reductions, a WT1-specific immune response, and a good safety profile. Therefore, WT1-targeting immunotherapy warrants further investigation in pediatric patients with relapsed DMG. [ABSTRACT FROM AUTHOR]

Published
2020
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49. Reader-free ELISPOT assay for immuno-monitoring in peptide-based cancer vaccine immunotherapy.

Author

Hayashi, Sae, Imanishi, Rin, Adachi, Mayuko, Ikejima, Sayaka, Nakata, Jun, Morimoto, Soyoko, Fujiki, Fumihiro, Nishida, Sumiyuki, Tsuboi, Akihiro, Hosen, Naoki, Nakajima, Hiroko, Hasegawa, Kana, Oka, Yoshihiro, Sugiyama, Haruo, and Oji, Yusuke

Subjects
CANCER vaccines, NEPHROBLASTOMA, IMMUNOTHERAPY, IMMUNE response, BACTERIAL vaccines, PARTICLE analysis
Abstract

Cancer vaccine immunotherapy is a therapy that induces cellular immune responses against a target molecule to elicit clinical anti-tumor effects. These cellular immune responses against the target molecule are monitored to evaluate whether the antigen-specific cellular immune responses are induced and maintained during the vaccination period. Enzyme-linked immunospot (ELISPOT) assay is widely performed to analyze not only the frequency of immune cells, but also their effector functions as determined by their cytokine production/secretion. The present study aimed to develop a reader-free ELISPOT assay using a handy membrane-punching device termed ELI 8. With the assistance of particle analysis by ImageJ software, the results of spot counting were reproducible with high inter-assay and inter-examiner concordance. Immune cells that produce and secrete Th1 cytokines without antigen-peptide stimulation of peripheral blood mononuclear cells (PBMCs) were detected, and their frequencies in patients with cancer were significantly higher compared with those in healthy individuals. These frequencies varied between individuals, as well as between time points during the course of cancer vaccine immunotherapy in each patient. Due to the variability in spontaneous cytokine production/secretion by PBMCs, an antigen-specific immune response (IR) index is proposed, which is a ratio of the number of spot-forming cells (SFCs) subjected to antigen-stimulation to that of SFCs with spontaneous cytokine secretion without antigen-stimulation. This index may be used as a marker for antigen-specific cellular immune responses in patients treated with cancer immunotherapy. The IR index successfully detected the induction of Wilms' tumor 1-specific cellular immune responses in patients with cancer treated with cancer vaccine immunotherapy. [ABSTRACT FROM AUTHOR]

Published
2020
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