2. CLINICAL SCIENCE

ANNUAL REPORT FOR JOINT PROJECT

  1. Title of Project: Evaluation of immunosurveillance mechanisms and its application to develop 2nd generation of tumor vaccine therapy protocol
  2. Duration: April 1, 2004 — March 31, 2006
  3. Project Organization
    1. Japanese Principal Investigator (JPI)
      Takashi Nishimura (Professor, Inst. for Genetic Medicine Hokkaido Univ. / Div. of Immunoregulation)
    2. U.S. Principal Investigator (USPI)
      Lloyd J. Old (Professor, Ludwig Institute for Cancer Research)
    3. Research Associate (Japanese / U.S.)
      Takemasa Tsuji (Post doctoral fellow, Inst. for Genetic Medicine Hokkaido Univ. / Div. of Immunoregulation)
  4. Number of Participants
    1) Japanese side:   16  persons 2) US side:  7  persons
  5. Number of Exchanges in JFY 2004
    1. from Japan to US

      Takemasa Tsuji (Inst. for Genetic Medicine Hokkaido Univ.)
      July 18 — July 25, The American Association of Immunologist 12th international Congress of Immunology

      Kenji Chamoto(Inst. for Genetic Medicine Hokkaido Univ.)
      July 18 — July 25, The American Association of Immunologist 12th international Congress of Immunology

      Takemasa Tsuji
      Sep. 29 — Oct. 1, Japanese Cancer Association, The 63rd annual meeting of the Japanese Cancer Association

      Takemasa Tsuji
      Oct. 3 — Oct. 7, Ludwig Inst. for Cancer Res.

      Hiroaki Ikeda
      Oct. 3 — Oct. 8, Ludwig Inst. for Cancer Res.

      Takashi Nishimura
      Dec. 8 — Dec. 12, Ludwig Inst. for Cancer Res.

    2. from US to Japan: None
  6. Activities of RA in JFY2004
    Research Associate, Takemasa Tsuji, worked in Inst. for Genetic Medicine, Hokkaido University in JFY 2004. He contributed in works to establish immunological monitoring system necessary for human cancer immunotherapy, human T cell lines specific for tumor antigens, and genetically engineered T cells that express tumor antigen specific TCR or CIR. He contributed in communication with Ludwig Institute for Cancer Research to share the techniques and the information of immunological monitoring and have been accelerating the collaborative work between Hokkaido Univ. and Ludwig Institute for Cancer Research. He has been joining with Ludwig Institute for Cancer Research in U.S. since April 2005, and will learn more techniques of both cellular and molecular immunology, and will further facilitate the collaboration of the two institutes.
  7. Status Report of Project Implementation and Scientific Achievements
    1. Basic research on cancer immunosurveillance and cancer immunoediting
      1. Analysis of the mechanisms of cancer immunosurveillance in tumor bearing host.
        Schreiber (Washington Univ.) and Ikeda (Hokkaido Univ.) has been studying the significance of the cancer immunoediting concept in tumor immunology (ref. 1, 2). They have compared the gene expression profiles between the tumors developed in immunocompetent mice and immunodeficient mice, and identified a subset of genes that are potential targets of the cancer immunoediting process. They are in process of evaluation of the physiological significance for each gene in cancer immunoediting process.
        Shiku (Mie Univ.), Nishikawa, Gnjatic, Ritter, and Old (Ludwig Inst. for Cancer research) addressed precise mechanisms of immunosuppression in tumor bearing hosts. Specifically, they defined the target antigens for naturally occurring CD4+ CD25+ regulatory T cells that suppress anti-tumor immune response in mouse model (ref.3). They also investigated the immunosuppression in tumor bearing state of humans, and demonstrated an important role for CD4+ CD25+ regulatory T cells in the control of the induction of antigen-specific CD4+ helper T cell response in cancer patients (ref. 4).
      2. Development of an effective tumor vaccine protocol in animal model.
        Nishimura, Ikeda, Tsuji, and Chamoto (Hokkaido Univ.) have revealed the importance of helper T cells and dendritic cells in anti-tumor immunity utilizing mouse models. They demonstrated the critical role of type-1 innate and acquired immunity in tumor immunotherapy (ref. 5). They have shown the effectiveness of the liposome-encapuslated CpG oligondeoxynucleotides as a potent adjuvant for inducing type 1 immunity (ref. 5, 6). These data strongly suggested that the strategy to use tumor antigen protein but not peptide with appropriate adjuvant such as CpG encapsulated with efficient delivery system such as liposome is an very attractive and promising method to achieve the development of an tumor vaccine protocol much more effective than existing protocols. They also established the method to efficiently generate human tumor-specific, HLA class I-restricted Th1 and Tc1 cells by cell engineering with tumor peptide-specific T cell receptor genes (ref. 7, 8).
    2. Clinical trial of cancer vaccine
      Nishimura, Akita, Ikeda, Tsuji, Chamoto (Hokkaido Univ.) planned a clinical trial of Immunization with NY-ESO-1 protein and cytosine-phosphorothioate-guanine (CpG) 7909 alone or encapsulated in liposome in patients with tumors expressing NY-ESO-1 antigen or LAGE-1 antigen. Hokkaido University Hospital and Nagoya University Hospital will participate as clinical sites, and Institute for Genetic Medicine, Hokkaido University and LICR will conduct molecular and immunological assays. Old et al. in Ludwig Institute for Cancer Research has established the system and facility to produce NY-ESO-1 protein in GMP level, which is available for this clinical trial. CpG in GMP level can be supplied from Coley Pharmaceutical Group, and Ludwig Institute for Cancer research and Hokkaido University made MTA with Coley Pharmaceutical Group about its transfer. Yoshida and Sato (Nagoya Univ.) have established the system and facility to produce liposome in GMP level, which is available for this trial. They are in process to validate the quality of the complex of NY-ESO-1 protein, CpG, and liposome.
      Nishimura, Akita, and Ikeda (Hokkaido Univ.) have established an organization for cancer vaccine and cell therapy projects in Hokkaido University which includes 12 clinical departments in Hokkaido University School of Medicine and department of immunoregulation in Institute for Genetic Medicine, Hokkaido University. From this organization, the final version of the protocol for the clinical trial was proposed to the PRC (Protocol Review Committee) board of Ludwig Institute for Cancer Research for the final review. This protocol was also proposed to the ethical committee of the Hokkaido University Graduate School of Medicine. It is expected that both of the committee will answer with their decision on the approval for the protocol within several months.
      Nishimura, Akita, Ikeda, Tsuji, and Chamoto (Hokkaido Univ.) examined the tumor samples (more than 200 samples) from cancer patients who had surgical resection of various types of cancer in recent several years with their expression of the two tumor antigens, NY-ESO-1 and LAGE-1. NY-ESO-1 was founded to be expressed in 29.4 % of esophagus cancer, 9.2 % of lung cancer, but not in other types of cancer including the cancer of stomach, bill duct, ovary, head and neck, and melanomas. LAEG-1 expression frequency appeared to be approximately same as that of NY-ESO-1. The expression of NY-ESO-1 in prostate cancer ad mammary cancer is also reported. These findings revealed the frequency of the expression of the two antigens in Japanese population, which is largely different from the expression frequency in Caucasians. These analyses also provided with the information of potential patients who will be able to enter to our clinical trial.
    ACHIEVEMENTS IN PUBLICATION
    1. Dunn, G. P., Old, L. J.,Schreiber, R. D.: The immunobiology of cancer immunosurveillance and immunoediting. Immunity, 21: 137-148, 2004.
    2. Schreiber, R. D.: Cancer vaccines 2004 opening address: the molecular and cellular basis of cancer immunosurveillance and immunoediting. Cancer Immun, 5 Suppl 1: 1, 2005.
    3. Nishikawa, H., Kato, T., Tawara, I., Saito, K., Ikeda, H., Kuribayashi, K., Allen, P. M., Schreiber, R. D., Sakaguchi, S., Old, L. J.,Shiku, H.: Definition of target antigens for naturally occurring CD4+ CD25+ regulatory T cells. J Exp Med, 201: 681-686, 2005.
    4. Nishikawa, H., Jager, E., Ritter, G., Old, L. J.,Gnjatic, S.: CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood, 2005. In press.
    5. Ikeda, H., Chamoto, K., Tsuji, T., Suzuki, Y., Wakita, D., Takeshima, T.,Nishimura, T.: The critical role of type-1 innate and acquired immunity in tumor immunotherapy. Cancer Sci, 95: 697-703, 2004.
    6. Suzuki, Y., Wakita, D., Chamoto, K., Narita, Y., Tsuji, T., Takeshima, T., Gyobu, H., Kawarada, Y., Kondo, S., Akira, S., Katoh, H., Ikeda, H.,Nishimura, T.: Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity. Cancer Res, 64: 8754-8760, 2004.
    7. Tsuji, T., Chamoto, K., Gyobu, H., Ikeda, H.,Nishimura, T.: Application of genetically engineered tumor-specific Th1 cells to adoptive tumor immunotherapy. Annals of Canscer Research and Therapy, 2005. In press.
    8. Tsuji, T., Yasukawa, M., Matsuzaki, J., Ohkuri, T., Chamoto, K., Wakita, D., Azuma, T., Niiya, H., Miyoshi, H., Kuzushima, K., Oka, Y., Sugiyama, H., Ikeda, H.,Nishimura, T.: Generation of human tumor-specific, HLA class I-restricted Th1 and Tc1 cells by cell engineering with tumor peptide-specific T cell receptor genes. Blood, 2005. In press.
  8. Any Comments
    A seminar entitled "Japan-US collaborative meeting for cancer immunosurveillance and cancer vaccine clinical trials" is planned to take place in Sapporo, Japan on 19th and 20th of August 2005 as a part of this joint project.