Division of Cancer Immunotherapy (Kashiwa Campus)

Tetsuya Nakatsura, Yasushi Uemura, Toshiaki Yoshikawa, Keigo Saito, Manami Shimomura, Rong Zhang, Toshihiro Suzuki, Nobuhiro Tsuchiya , Yoshitaka Tada, Tatsuaki Iwama, Shoichi Mizuno, Yumi Tokumitsu, Kayoko Shoda, Yukiko Kozaki, Norihiro Fujinami, Shiori Sugai, Megumi Ozaki

Introduction

The Division of Cancer Immunology aims to investigate evidence-based cancer immunotherapy, repeating basic research and translational research. This Division is focused on developing not only more effective immunotherapies, but also immunological methods for the suppression of recurrence or for cancer prevention.

Research activities

1)A First-in-human clinical Phase I investigator initiated trial using original peptide vaccine derived from HSP105 for patients with advanced esophageal / colorectal cancer was conducted.

2)A paper of the GPC3 peptide vaccine clinical trial conducted at Nagoya University was published.

3)We prepared a first-in-human clinical Phase I investigator initiated trial using anti-CD4 antibody with Prof. Matsushima of the University of Tokyo and others. It will start soon. Also, a paper showing the effectiveness of combination therapy of peptide vaccine and anti-CD4 antibody was published.

4)We created an original therapeutic anti-GPC3 antibody in cooperation with Prof. Tamada at Yamaguchi University and filed a patent.

5)We are preparing the first clinical application of FITC-CAR-T therapy within one year by changing the target to CD 20 from GPC3 first in cooperation with Prof. Tamada at Yamaguchi University.

6)We are developing iPS cell-derived CAR-T cell therapy targeting GPC3 in cooperation with Dr. Kaneko at CiRA of Kyoto University.

7)For iPS cell-derived TCR-T cell therapy targeted to GPC3, collaborative research with Kyoto University and Takeda Pharmaceutical Co., Ltd. was started. We also applied for a patent on the TCR sequence, and we are pursuing the clinical application.

8)We are aiming for FIH clinical Phase I investigator initiated trial using IFN-releasing iPS cell derived myeloid cell line developed by Dr. Senju at Kumamoto University.

9)In addition, various immune cells derived from iPS cells for cancer treatment are prepared and their usefulness is studied at the basic research level.

10)We discovered a cytotoxic method against undifferentiated iPS cells to solve the concern of the induction of canceration in regenerative transplantation medicine using iPS cells in collaboration with Prof. Fukuda at Keio University, and applied for a patent.

11)We proved the usefulness of GPC3 as a predictive marker for hepatocellular carcinoma recurrence in collaboration with Sysmex, and applied for a patent.

Clinical trials

We are performing a phase I study of HSP105 peptide vaccine for patients with esophageal cancer and colorectal cancer.

Education

Our Division accepted and trained the following Trainees: Doctral course of Graduate School of Medicine, Yokohama City University (1), Nagoya University Graduate School of Medicine (1), Tokyo University of Science (2), Master course of Tokyo University of Science (1), and the University of Nantes in France (1).

Future prospects

Immune check point blockade such as anti-PD-1 antibody or anti-PD-L1 antibody, and CAR-T cell therapy targeting CD 19 showed high clinical effect, therefore the development of innovative cancer immunotherapy is required. We continue to practice activities of bridging basic researches and clinical applications aiming at the development of novel immunotherapeutic methods.

List of papers published in 2016

Journal

1.Suzuki S, Sakata J, Utsumi F, Sekiya R, Kajiyama H, Shibata K, Kikkawa F, Nakatsura T. Efficacy of glypican-3-derived peptide vaccine therapy on the survival of patients with refractory ovarian clear cell carcinoma. Oncoimmunology, 5:e1238542, 2016

2.Arai K, Eguchi T, Rahman MM, Sakamoto R, Masuda N, Nakatsura T, Calderwood SK, Kozaki K, Itoh M. A Novel High-Throughput 3D Screening System for EMT Inhibitors: A Pilot Screening Discovered the EMT Inhibitory Activity of CDK2 Inhibitor SU9516. PLoS One, 11:e0162394, 2016

3.Fujinami N, Sawada Y, Nobuoka D, Nakatsura T. Enhancing the anti-tumor effects of cancer peptide vaccine therapy. J Vaccines Vaccin, 7: 1000330, 2016

4.Maekawa A, Kohashi K, Kuda M, Iura K, Ishii T, Endo M, Nakatsura T, Iwamoto Y, Oda Y. Prognostic significance of FOXM1 expression and antitumor effect of FOXM1 inhibition in synovial sarcomas. BMC Cancer, 16:511, 2016

5.Sugai S, Yoshikawa T, Iwama T, Tsuchiya N, Ueda N, Fujinami N, Shimomura M, Zhang R, Kaneko S, Uemura Y, Nakatsura T. Hepatocellular carcinoma cell sensitivity to Vgamma9Vdelta2 T lymphocyte-mediated killing is increased by zoledronate. Int J Oncol, 48:1794-1804, 2016

6.Kuda M, Kohashi K, Yamada Y, Maekawa A, Kinoshita Y, Nakatsura T, Iwamoto Y, Taguchi T, Oda Y. FOXM1 expression in rhabdomyosarcoma: a novel prognostic factor and therapeutic target. Tumour Biol, 37:5213-5223, 2016

7.Fujinami N, Yoshikawa T, Sawada Y, Shimomura M, Iwama T, Sugai S, Kitano S, Uemura Y, Nakatsura T. Enhancement of antitumor effect by peptide vaccine therapy in combination withanti-CD4antibody: Study in a murine model. Biochemistry and Biophysics Reports, 5:482-491, 2016

8.Sawada Y, Yoshikawa T, Ofuji K, Yoshimura M, Tsuchiya N, Takahashi M, Nobuoka D, Gotohda N, Takahashi S, Kato Y, Konishi M, Kinoshita T, Ikeda M, Nakachi K, Yamazaki N, Mizuno S, Takayama T, Yamao K, Uesaka K, Furuse J, Endo I, Nakatsura T. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunology, 5:e1129483, 2016

9.Iwama T, Uchida T, Sawada Y, Tsuchiya N, Sugai S, Fujinami N, Shimomura M, Yoshikawa T, Zhang R, Uemura Y, Nakatsura T. Vaccination with liposome-coupled glypican-3-derived epitope peptide stimulates cytotoxic T lymphocytes and inhibits GPC3-expressing tumor growth in mice. Biochem Biophys Res Commun, 469:138-143, 2016

10.Maekawa A, Kohashi K, Setsu N, Kuda M, Iura K, Ishii T, Matsunobu T, Nakatsura T, Iwamoto Y, Oda Y. Expression of Forkhead box M1 in soft tissue leiomyosarcoma: Clinicopathologic and in vitro study using a newly established cell line. Cancer Sci, 107:95-102, 2016

11.Sayem MA, Tomita Y, Yuno A, Hirayama M, Irie A, Tsukamoto H, Senju S, Yuba E, Yoshikawa T, Kono K, Nakatsura T, Nishimura Y. Identification of glypican-3-derived long peptides activating both CD8+ and CD4+ T cells; prolonged overall survival in cancer patients with Th cell response. Oncoimmunology, 5:e1062209, 2016

12.Miyasaka T, Watanabe Y, Akahoria Y, Miyamura N, Ishiia K, Kinjo Y, Miyazaki Y, Liu T-Y, Uemura Y, and Kawakami K. Human CD4- CD8- invariant natural killer T cells promote IgG secretion from B cells stimulated by cross-linking of their antigen receptors. World J Vaccines, 6:34-41, 2016

13.Kitayama S, Zhang R, Liu TY, Ueda N, Iriguchi S, Yasui Y, Kawai Y, Tatsumi M, Hirai N, Mizoro Y, Iwama T, Watanabe A, Nakanishi M, Kuzushima K, Uemura Y, Kaneko S. Cellular Adjuvant Properties, Direct Cytotoxicity of Re-differentiated Vα24 Invariant NKT-like Cells from Human Induced Pluripotent Stem Cells. Stem Cell Reports, 6:213-227, 2016

14.Nakatsuka R, Iwaki R, Matsuoka Y, Sumide K, Kawamura H, Fujioka T, Sasaki Y, Uemura Y, Asano H, Kwon AH, Sonoda Y. Identification and characterization of lineage-CD45-Sca-1+ VSEL phenotypic cells residing in adult mouse bone tissue. Stem Cells Dev, 25:27-42, 2016