Analysis of B cell repertoires and their antigen specificity in peripheral blood from cancer patients undergoing anti-PD-1 antibody therapy.

• Project/Area Number: 18K19490
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Kanagawa Cancer Center Research Institute
• Principal Investigator: Sasada Tetsuro 地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所), がんワクチン・免疫センター, 部長 (70293967)
• Co-Investigator(Kenkyū-buntansha): 紅露 拓 地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所), 臨床研究所, 技師・研究員 (90372424)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 抗PD-1抗体 / B細胞 / B細胞受容体レパトア / 抗原 / バイオマーカー / 免疫チェックポイント阻害剤 / 抗腫瘍効果 / 有害事象 / B細胞受容体 / レパトア / Ｂ細胞 / Ｂ細胞受容体

Outline of Final Research Achievements

In this study, we have examined the clinical significance of analysis of B cell receptor (BCR) repertoires in peripheral blood from cancer patients undergoing anti-PD-1 antibody therapy. In patients with non-small cell lung cancer (n=30), the diversity of BCR repertoires was significantly reduced in those with better anti-tumor responses. In contrast, in patients with urothelial cancer (n=26), the diversity of BCR repertoires was significantly reduced in those with adverse events. Based on these results, the analysis of BCR repertoires might be clinically useful as a biomarker of immune checkpoint blockade. We are now trying to identify the antigens recognized by BCR from B cells selectively expanded in patients with better anti-tumor responses or adverse events after treatment to elucidate the mechanisms of anti-PD-1 antibody therapy.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果から、BCRレパトア解析のバイオマーカーとしての有用性が示唆された。なお、BCRレパトア多様性の臨床的意義はがん種により異なる可能性があるため、さらに詳細な検討が望まれるが、新たな視点から免疫チェックポイント（PD-1/PD-L1）研究の展開が期待できる。本研究の成果は、抗PD-1抗体の作用メカニズムを解明するとともに、不必要な治療による不利益（有害事象合併・医療費浪費）の回避にもつながる可能性があり、臨床的意義は大きいと思われる。

Research Products

• [Journal Article] Identification of biomarkers for personalized peptide vaccination in 2,588 cancer patients (2020)
  • Author(s): Suekane Shigetaka、Yutani Shigeru、Yamada Akira、Sasada Tetsuro、Matsueda Satoko、Takamori Shinzo、Toh Uhi、Kawano Kouichiro、Yoshiyama Koichi、Sakamoto Shinjiro、Sugawara Shunichi、Komatsu Nobukazu、Yamada Teppei、Naito Masayasu、Terasaki Mizuhiko、Mine Takashi、Itoh Kyogo、Shichijo Shigeki、Noguchi Masanori
  • Journal Title: International Journal of Oncology Volume: 56 Pages: 1479-1489
  • DOI: 10.3892/ijo.2020.5019
  • Peer Reviewed / Open Access
• [Journal Article] Distribution of Regulatory T-Cells and Other Phenotypes of T-Cells in Tumors and Regional Lymph Nodes of Colorectal Cancer Patients. (2020)
  • Author(s): Kazama K, Otake J, Satoyoshi T, Shiozawa M, Sugano N, Sato S, Atsumi Y, Kano K, Murakawa M, Maezawa Y, Hashimoto I, Numata M, Oshima T, Yukawa N, Rino Y, Sasada T, Masuda M.
  • Journal Title: In Vivo. Volume: 34 Issue: 2 Pages: 849-856
  • DOI: 10.21873/invivo.11848
  • Peer Reviewed / Open Access
• [Journal Article] Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: a randomized phase II trial (2020)
  • Author(s): Noguchi Masanori、Arai Gaku、Egawa Shin、Ohyama Chikara、Naito Seiji、Matsumoto Kazumasa、Uemura Hirotsugu、Nakagawa Masayuki、Nasu Yasutomo、Eto Masatoshi、Suekane Shigetaka、Sasada Tetsuro、Shichijo Shigeki、Yamada Akira、Kakuma Tatsuyuki、Itoh Kyogo
  • Journal Title: Cancer Immunology, Immunotherapy Volume: 69 Issue: 5 Pages: 847-857
  • DOI: 10.1007/s00262-020-02498-8
  • Peer Reviewed / Open Access
• [Journal Article] High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer. (2020)
  • Author(s): Ohkuma R, Yada E, Ishikawa S, Komura D, Ishizaki H, Tamada K, Kubota Y, Hamada K, Ishida H, Hirasawa Y, Ariizumi H, Satoh E, Shida M, Watanabe M, Onoue R, Ando K, Tsurutani J, Yoshimura K, Yokobori T, Sasada T, Aoki T, Murakami M, Norose T, Ohike N, Takimoto M, Izumizaki M, Kobayashi S, Tsunoda T, Wada S.
  • Journal Title: PLoS One Volume: 10 Issue: 1 Pages: e0226707-e0226707
  • DOI: 10.1371/journal.pone.0226707
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heat shock protein 105 peptide vaccine could induce antitumor immune reactions in a phase I clinical trial (2019)
  • Author(s): Shimizu Yasuhiro、Yoshikawa Toshiaki、Kojima Takashi、Shoda Kayoko、Nosaka Kazuto、Mizuno Shoichi、Wada Satoshi、Fujimoto Yuki、Sasada Tetsuro、Kohashi Kenichi、Bando Hideaki、Endo Itaru、Nakatsura Tetsuya
  • Journal Title: Cancer Science Volume: 110 Issue: 10 Pages: 3049-3060
  • DOI: 10.1111/cas.14165
  • Peer Reviewed / Open Access
• [Journal Article] Immunological consequences following splenectomy in patients with liver cirrhosis. (2019)
  • Author(s): Hirakawa Y, Ogata T, Sasada T, Yamashita T, Itoh K, Tanaka H, Okuda K.
  • Journal Title: Exp Ther Med. Volume: 18 Pages: 848-856
  • DOI: 10.3892/etm.2019.7640
  • Peer Reviewed / Open Access
• [Journal Article] Prospects for a personalized peptide vaccine against lung cancer. (2019)
  • Author(s): Nakahara Y, Kouro T, Igarashi Y, Kawahara M, Sasada T.
  • Journal Title: Expert Rev Vaccines. Volume: 18 Issue: 7 Pages: 703-709
  • DOI: 10.1080/14760584.2019.1635461
  • Peer Reviewed
• [Journal Article] 遺伝子変異由来ネオアンチゲンを標的とした特異的免疫療法. (2019)
  • Author(s): 紅露拓，笹田哲朗
  • Journal Title: 医学のあゆみ Volume: 271 Pages: 163-168
• [Journal Article] がん免疫療法のバイオマーカーの現状および今後の展望. (2019)
  • Author(s): 松尾規和，笹田哲朗
  • Journal Title: 実験医学 増刊 「がん免疫療法の個別化を支える新・腫瘍免疫学」 Volume: 37 Pages: 180-188
• [Journal Article] Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor. (2019)
  • Author(s): Matsuo N, Azuma K, Hattori S, Ohtake J, Kawahara A, Ishii H, Tokito T, Yamada K, Shibata Y, Shimokawaji T, Kondo T, Kato T, Saito H, Yamada K, Sasada T, Hoshino T.
  • Journal Title: Int J Cancer. Volume: 144 Issue: 5 Pages: 1170-1179
  • DOI: 10.1002/ijc.31923
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of soluble immune mediators as potential biomarkers during immune checkpoint inhibitor therapy. (2019)
  • Author(s): Matsuo N, Azuma K, Sasada T.
  • Journal Title: Oncotarget. Volume: 10 Issue: 20 Pages: 1866-1867
  • DOI: 10.18632/oncotarget.26749
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Novel HLA Class II-Restricted Neoantigens Derived from Driver Mutations (2019)
  • Author(s): Iiizumi Susumu、Ohtake Junya、Murakami Naoko、Kouro Taku、Kawahara Mamoru、Isoda Fumiko、Hamana Hiroshi、Kishi Hiroyuki、Nakamura Norihiro、Sasada Tetsuro
  • Journal Title: Cancers Volume: 11 Issue: 2 Pages: 266-266
  • DOI: 10.3390/cancers11020266
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced expression of PD-L1 in non-muscle-invasive bladder cancer after treatment with Bacillus Calmette-Guerin. (2018)
  • Author(s): Hashizume A, Umemoto S, Yokose T, Nakamura Y, Yoshihara M, Shoji K, Wada S, Miyagi Y, Kishida T, Sasada T.
  • Journal Title: Oncotarget. Volume: 9 Issue: 75 Pages: 34066-34078
  • DOI: 10.18632/oncotarget.26122
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel HLA-A24-restricted cytotoxic T lymphocyte epitope peptide derived from mesothelin in pancreatic cancer. (2018)
  • Author(s): Tsukagoshi M, Wada S, Hirono S, Yoshida S, Yada E, Sasada T, Shirabe K, Kuwano H, Yamaue H.
  • Journal Title: Oncotarget. Volume: 9 Issue: 59 Pages: 31448-31458
  • DOI: 10.18632/oncotarget.25837
  • Peer Reviewed / Open Access
• [Journal Article] A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma. (2018)
  • Author(s): Narita Y, Arakawa Y, Yamasaki F, Nishikawa R, Aoki T, Kanamori M, Nagane M, Kumabe T, Hirose Y, Ichikawa T, Kobayashi H, Fujimaki T, Goto H, Takeshima H, Ueba T, Abe H, Tamiya T, Sonoda Y, Natsume A, Kakuma T, Sugita Y, Komatsu N, Yamada A, Sasada T, Matsueda S, Shichijo S, Itoh K, Terasaki M.
  • Journal Title: Neuro Oncol. Volume: 21 Issue: 3 Pages: 348-359
  • DOI: 10.1093/neuonc/noy200
  • Peer Reviewed / Open Access
• [Journal Article] がんワクチン療法の将来 (2018)
  • Author(s): 飯泉 晋, 中村徳弘, 笹田哲朗.
  • Journal Title: 腫瘍内科 Volume: 22 Pages: 135-141
• [Presentation] High expression of Olfactomedin-4 correlates with chemoresistance and poor prognosis for pancreatic cancer. (2019)
  • Author(s): Ryotaro Ohkuma, Erica Yada, Yutaro Kubota, Kazuyuki Hamada, Hiroo Ishida, Yuya Hirasawa, Hirotsugu Ariizumi, Etsuko Satoh, Junji Tsurutani, Kiyoshi Yoshimura, Tetsuro Sasada, Takeshi Aoki, Masahiko Murakami, Tomoko Norose, Nobuyuki Ohike, Masafumi Takimoto, Takuya Tsunoda, Satoshi Wada.
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Early changes in plasma CXCL2 and MMP2 levels predicts the response to anti-PD-1 therapy in non-small-cell lung cancer. (2019)
  • Author(s): Matsuo N, Azuma K, Murotani K, Ishii H, Tokito T, Yamada K,Shibata Y, Shimokawaji T, Nakahara Y, Kondo T, Kato T, Saito H, Yamada K, Sasada T, Hoshino T.
  • Organizer: 2019 World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] Changes of BCR Repertoire Are Predictive Biomarker for the Efficacy of Immune Checkpoint Inhibitor in NSCLC. (2019)
  • Author(s): Azuma K, Nakahara Y, Matsuo N, Ishii H, Tokito T, Murotani K, Hoshino T, Sasada T.
  • Organizer: 2019 World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] Immunogenicity of HLA class II-restricted neoantigens derived from driver mutations. (2019)
  • Author(s): Sasada T, Iiizumi S, Kouro T, Kawahara M, Nakamura N.
  • Organizer: Fifth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference
  • Int'l Joint Research
• [Presentation] Proteogenomics-based identifying neoantigens in refractory cancers using xenograft mice. (2019)
  • Author(s): Yuko Nakamura, Susumu Iizumi, Hiroki Ueda, Shogo Yamamoto, Kenji Tatsuno, Aya Nakayama, Kazuki Yamamoto, Taku Koro, Kyoko Hasegawa, Norihiro Nakamura, Hiroyuki Aburatani, Tetsuro Sasada, Takeshi Kawamura.
  • Organizer: 18th Human Proteome Organization World Congress
  • Int'l Joint Research
• [Presentation] A novel affinity-enhanced NY-ESO-1-targeting TCR-redirected T cell transfer exhibited early-onset cytokine release syndrome and subsequent tumor responses in synovial sarcoma patients. (2019)
  • Author(s): Hattori H, Ishihara M, Kitano S, Miyahara Y, Kato H, Mishima H, Yamamoto N, Funakoshi T, Kojima T, Sasada T, Sato E, Okamoto S, Tomura D, Chono H, Nukaya I, Mineno J, Ikeda H, Watanabe T, Kageyama S, Shiku H.
  • Organizer: ESMO 2019 Congress
  • Int'l Joint Research
• [Presentation] Tumor responses and early onset cytokine release syndrome in synovial sarcoma patients treated with a novel affinityenhanced NY-ESO-1-targeting TCR-redirected T cell transfer. (2019)
  • Author(s): Ishihara M, Kitano S, Hattori H, Miyahara Y, Kato H, Mishima H, Yamamoto N, Funakoshi T, Kojima T, Sasada T, Sato E, Okamoto S, Tomura D, Chono H, Nukaya I, Mineno J, Ikeda H, Watanabe T, Kageyama S, Shiku H.
  • Organizer: ASCO Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Changes in plasma CXCL2 and MMP2 levels reflect response to anti-PD-1 therapy in non-small-cell lung cancer patients. (2019)
  • Author(s): Norikazu Matsuo, Koichi Azuma, Kenta Murotani, Yoshiko Naito, Hidenobu Ishii, Takaaki Tokito, Tadasuke Shimokawaji, Yoshiro Nakahara, Tetsuro Kondo, Terufumi Kato Haruhiro Saito, Kouzo Yamada, Tetsuro Sasada, Tomoaki Hoshino.
  • Organizer: 第17回日本臨床腫瘍学会学術集会
• [Presentation] Changes of BCR repertoire are predictive biomarker for the efficacy of immune checkpoint inhibitor in NSCLC. (2019)
  • Author(s): Yoshiro Nakahara, Norikazu Matsuo, Koichi Azuma, Yoshiko Naito, Hidenobu Ishii, Takaaki Tokito, Yuka Igarashi, Taku Kouro, Ryo Usui, Tadasuke Shimokawaji, Tetsuro Kondo, Terufumi Kato, Haruhiro Saito, Kouzo Yamada, Tomoaki Hoshino, Tetsuro Sasada.
  • Organizer: 第17回日本臨床腫瘍学会学術集会
• [Presentation] Immunogenicity of frequent driver mutations; identification of novel HLA class II-restricted neoantigens. (2019)
  • Author(s): Susumu Iiizumi, Junya Ohtake, Taku Kouro, Mamoru Kawahara, Yuka Igarashi, Norihiro Nakamura, Tetsuro Sasada.
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] B細胞受容体(BCR)のレパトア解析は非小細胞肺がんにおける免疫チェックポイント阻害剤のバイオマーカーとして有用である (2019)
  • Author(s): 五十嵐 友香, 中原 善朗, 松尾 規和, 東 公一, 笹田 哲朗
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] Optimization of chimeric antigen receptor construct targeting malignant mesothelioma antigen. (2019)
  • Author(s): Taku Kouro, Shoutaro Tsuji, Kohzoh Imai, Tetsuro Sasada.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Optimization of CAR T cells recognizing malignant mesothelioma specific antigen. (2019)
  • Author(s): Taku Kouro, Kohzoh Imai, Tetsuro Sasada.
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Enhanced lymphocyte accumulation through chemokine overexpression in tumor microenvironment. (2019)
  • Author(s): Yuka Igarashi, Junya Ohtake, Yuki Fujimoto, Tetsuro Sasada.
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Potential biomarkers in non-small cell lung cancer patients treated with anti-PD-1 inhibitors. (2018)
  • Author(s): Norikazu Matsuo, Koichi Azuma, Junya Ohtake, Tetsuro Sasada.
  • Organizer: 第22回日本がん免疫学会総会
• [Presentation] Inflammatory soluble factors as potential biomarkers in non-small cell lung cancer treated with anti-PD-1 inhibitors. (2018)
  • Author(s): Tetsuro Sasada, Norikazu Matsuo, Junya Ohtake, Koichi Azuma.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Identification of therapeutic-specific mutations induced by anti-cancer drug using pancreatic cancer xenograft. (2018)
  • Author(s): Erica Yada, Tetsuro Sasada, Satoshi Wada.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Immunogenicity and specificity of neoantigens derived from tumor-specific mutations in gastric cancer. (2018)
  • Author(s): Sasada T, Ohtake J, Iizumi S, Kouro T, Igarashi Y, Kawahara M, Yada E.
  • Organizer: The 33rd Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2018)
  • Int'l Joint Research
• [Presentation] Identification of therapeutic-specific mutations induced by gemcitabine and nab-Paclitaxel in pancreatic cancer. (2018)
  • Author(s): Erica Yada, Taku Kouro,Tetsuro Sasada, Satoshi Wada.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Generation of CAR T cells recognizing malignant mesothelioma specific antigen (2018)
  • Author(s): Taku Kouro, Erica Yada, Mamoru Kawahara, Kozo Imai, Tetsuro Sasada.
  • Organizer: 第47回日本免疫学会学術集会
• [Book] プレシジョン・メディシン ～ビッグデータの構築・分析から臨床応用・課題まで～. (第2編 第3章 第3節) 変異遺伝子を標的とした個別化がん免疫療法の開発. (2018)
  • Author(s): 紅露拓，笹田哲朗.
  • Total Pages: 406
  • Publisher: エヌ・ティー・エス
• [Book] がん治療で起こる副作用・合併症の 治療法と薬剤開発. (第4章 11節) がんワクチン (2018)
  • Author(s): 和田聡, 笹田哲朗
  • Total Pages: 508
  • Publisher: 技術情報協会
  • ISBN: 9784861047237
• [Remarks] 研究室（神奈川県立がんセンター臨床研究所 がん免疫療法研究開発学部］ホームページ
  • URL: http://kcch.kanagawa-pho.jp/kccri/organization/menekiryoho.html
• [Remarks] 研究室（神奈川県立がんセンター臨床研究所 がん免疫療法研究開発学部）ホームページ
  • URL: http://kcch.kanagawa-pho.jp/kccri/organization/menekiryoho.html
• [Patent(Industrial Property Rights)] がん免疫療法の予後予測のためのバイオマーカー (2018)
  • Inventor(s): 笹田哲朗、東公一、松尾規和、星野友昭
  • Industrial Property Rights Holder: 地方独立行政法人神奈川県立病院機構、久留米大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas