Clinical studies of dendritic cell therapy for malignancies and their evaluation

• Project/Area Number: 16390198
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General internal medicine (including Psychosomatic medicine)
• Research Institution: The University of Tokyo
• Principal Investigator: YAMASHITA Naohide The University of Tokyo, Institute of Medical Science, Professor, 医科学研究所, 教授 (90174680)
• Co-Investigator(Kenkyū-buntansha): NAKAOKA Takashi The University of Tokyo, Institute of Medical Science, Lecturer, 医科学研究所, 講師 (80241256) ; 西下 聡英 東京大学, 医科学研究所, 助手 (10292864)
• Project Period (FY): 2004 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥13,800,000 (Direct Cost: ¥13,800,000); Fiscal Year 2006: ¥4,500,000 (Direct Cost: ¥4,500,000); Fiscal Year 2005: ¥4,500,000 (Direct Cost: ¥4,500,000); Fiscal Year 2004: ¥4,800,000 (Direct Cost: ¥4,800,000)
• Keywords: dendritic cell / CAII / endothelial cells / malignant melanoma / tumor-associated antigen / 甲状腺癌 / 抗体 / carbonic anhydrase II / 腫瘍血管 / プロテオミクス / α-enolase

Research Abstract

Recent progress of imagings and endoscopy enables us to detect cancers at early stages, which has brought out favorable prognosis of early cancers. However, prognosis of advanced cancers is not always good in spite of recent advances in medical technologies and regimens. For such intractable malignancies development of new therapies are desired and much attention has been paid to cancer immunotherapy using dendritic cells (DC). We have carried out DC therapy in ten stage IV melanoma patients and six thyroid cancer patients with distant metastasis. We used tumor lysate as tumor antigen. In the melanoma study one patient was stable disease, two, mixed response, and seven, progressive disease. In the thyroid study two patients were stable disease and four, progressive disease. In two melanoma patients who showed mixed response shrinkage or disappearance of metastatic tumors with massive necrosis occurred. In this study, we found a 29-kDa protein against which antibody was elicited by dend ritic cell therapy in one of the two patients. Matrix-assisted laser desorption ionization-time of flight/mass spectrometry analysis of the protein isolated by two-dimensional electrophoresis combined with Western blots revealed that the 29-kDa protein was carbonic anhydrase II (CA-II). Immunohistochemistry of the tumors and normal tissues showed that CA-II was expressed in the tumor vessel but not in normal vessel endothelium. CA-II expression in tumor endothelium was observed as well in other cancers including esophageal, renal, and lung cancers. In an in vitro angiogenesis model, CA-II expression of normal human vein endothelial cells was significantly up-regulated when cells were cultured in the acidic and hypoxic conditions indicative of a tumor environment. These findings suggest that CA-II is a tumor vessel endothelium-associated antigen in melanoma and other cancers, and elicitation of serum anti-CA-II antibody by dendritic cell therapy may be associated with good clinical outcome including tumor reduction.

Research Products

• [Journal Article] Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer (2007)
  • Author(s): Kuwabara, K
  • Journal Title: Thyroid. 17 Pages: 53-58
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer. (2007)
  • Author(s): K.Kuwabara, T.Nishishita, M.Morishita, N.Oyaizu, S.Yamashita, T.Kanematsu, T.Obara, Y.Mimura, Y.Inoue, M.Kaminishi, K.Koko, N.Amino, M.Kitaoka, K.Ito, A.Miyauchi, S.Noguchi, K.Uchimaru, E.Akagawa, N.Watanabe, TA.Takahashi, K.Sato, T.Inazawa, T.Nakaoka, N.Yamashita
  • Journal Title: Thyroid 17 Pages: 53-58
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer (2007)
  • Author(s): K Kuwabara, N Yamashita, et al.
  • Journal Title: Thyroid (印刷中)
• [Journal Article] Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response (2006)
  • Author(s): Fujita, S
  • Journal Title: Blood 107 Pages: 3656-3664
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of CCL21 and CCL19 in allergic inflammation in the ovalbumin-specific murine asthmatic model (2006)
  • Author(s): Yamashita, N
  • Journal Title: J Allergy Clin Immunol 117 Pages: 1040-1046
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response. (2006)
  • Author(s): S.Fujita, K.Seino, K.Sato, Y.Sato, K.Eizumi, N.Yamashita, M.Taniguchi, K.Sato
  • Journal Title: Blood 107 Pages: 3656-64
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of CCL21 and CCL19 in allergic inflammation in the ovalbumin-specific murine asthmatic model. (2006)
  • Author(s): N.Yamashita, H.Tashimo, Y.Matsuo, H.Ishida, K.Yoshiura, K.Sato, N.Yamashita, T.Kakiuchi, K.Ohta
  • Journal Title: J Allergy Clin Immunol 117 Pages: 1040-6
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response (2006)
  • Author(s): S Fujita, N Yamashita, et al.
  • Journal Title: Blood 107 Pages: 3656-3664
• [Journal Article] Role of CCL2 and CCL19 in allergic inflammation in the ovalbumin-specific murine asthmatic model (2006)
  • Author(s): N Yamashita, H Tashimo, et al.
  • Journal Title: J Allergy Clin Immunol 117 Pages: 1040-1046
• [Journal Article] TRAIL-transduced dendritic cells protect mice from acute graft-versus-host disease and leukemia relapse (2005)
  • Author(s): Sato, K
  • Journal Title: J. Immunol. 174 Pages: 4025-4033
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Frequent immune responses to a cancer/testis antigen CAGE in patients with microsatellite instability-positive endometrial cancer (2005)
  • Author(s): Iwata, T
  • Journal Title: Clinical Cancer Research. 11 Pages: 3949-3957
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Carbonic anhydrase-II is a tumor vessel endothelium-associated antigen targeted by dendritic cell therapy (2005)
  • Author(s): Yoshiura, K
  • Journal Title: Clinical Cancer Research 11 Pages: 8201-8207
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TRAIL-transduced dendritic cells protect mice from acute graft-versus-host disease and leukemia relapse. (2005)
  • Author(s): Sato, K., Nakaoka, T., Yamashima, N., Yagita, H., Kawasaki, H., Morimoto, C., Baba, M., Matsuyama, T.
  • Journal Title: J.Immunol. 174 Pages: 4025-33
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Frequent immune responses to a cancer/testis antigen CAGE in patients with microsatellite instability-positive endometrial cancer. (2005)
  • Author(s): T.Iwata, T.Fujita, N.Hirao, Y.Matsuzaki, T.Okada, H.Mochimaru, N.Susumu, E.Matsumoto, K.Sugano, N.Yamashita, S.Nozawa, Y.Kawakami
  • Journal Title: Clin.Cancer Res. 11 Pages: 3949-57
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Carbonic anhydrase-II is a tumor vessel endothelium-associated antigen targeted by dendritic cell therapy. (2005)
  • Author(s): K.Yoshiura, T.Nakaoka, T.Nishishita, K.Sato, A.Yamamoto, S.Shimada, T.Saida, Y.Kawakami, T.A.Takahashi, H.Fukuda, S.Imajoh-Ohmi, N.Oyaizu, N.Yamashita
  • Journal Title: Clin.Cancer Res. 11 Pages: 8201-7
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Carbonic anhydrase-II is a tumor vessel endothelium-associated antigen targeted by dendritic cell therapy (2005)
  • Author(s): Yoshiura K., Nakaoka T., et al.
  • Journal Title: Clinical Cancer Research 11 Pages: 8201-8207
• [Journal Article] TRAIL-transduced dendritic cells protect mice from acute graft-versus-host disease and leukemia relanse (2005)
  • Author(s): Sato K., Nakaoka T., et al.
  • Journal Title: Journal of immunology 174 Pages: 4025-4033
• [Journal Article] Frequent immune responses to a cancer/testis antigen CAGE in patients with microsatellite instability-positive endometrial cancer (2005)
  • Author(s): Iwata T., Fujita, T., et al.
  • Journal Title: Clinical Cancer Research 11 Pages: 3949-3957
• [Journal Article] TRAIL-transduced dendritic cells protect mice from acute graft-versus-host disease and leukemia relapse (2005)
  • Author(s): Sato K., Nakaoka T., et al.
  • Journal Title: Journal of immunology (In press)
• [Journal Article] Thyroglobulin-pulsed human monocyte-derived dendritic cells induce CD4^+Tcell activation (2004)
  • Author(s): Morishita, M
  • Journal Title: International Journal of Molecular Medicine 13 Pages: 33-39
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential Regulation of Cell Migration and Proliferation through Pyk2 in Endothelial Cells (2004)
  • Author(s): Kuwabara, K
  • Journal Title: Endocrinology 145 Pages: 3324-3330
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Phase I Study of Autologous Tumor Vaccines Transduced with the GM-CSF Gene in Four Patients with Stage IV Renal Cell Cancer in Japan (2004)
  • Author(s): Tani, K
  • Journal Title: Molecular Therapy 10 Pages: 799-816
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibitory effect of low-dose estrogen on neointimal formation after balloon injury of rat carotid artery (2004)
  • Author(s): Watanabe, T
  • Journal Title: Eur. J. Pharmacol. 502 Pages: 265-270
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Caveolin-1, Id3a and two LIM protein genes are upregulated by estrogen in vascular smooth muscle cells (2004)
  • Author(s): Watanabe T
  • Journal Title: Life Sci 75 Pages: 1219-1229
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A potential pro-angiogenic cell therapy with human placenta-derived mesenchymal cells (2004)
  • Author(s): Nishishita, T
  • Journal Title: Biochem. Biophysic. Res. Commun. 325 Pages: 24-31
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Thyroglobulin-pulsed human monocyte-derived dendritic cells induce CD4^+T cell activation (2004)
  • Author(s): Morishita M., Uchimaru K., Sato K., Yamashita S., Kanematsu T., Yamashita N.
  • Journal Title: Intern.J.Mol.Med. 13 Pages: 33-39
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Differential Regulation of Cell Migration and Proliferation through Pyk2 in Endothelial Cells. (2004)
  • Author(s): Kuwabara K, Nakaoka T, Sato K, Nishishita T, Sasaki T, Yamashita N.
  • Journal Title: Endocrinol. 145 Pages: 3324-30
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Phase I Study of Autologous Tumor Vaccines Transduced with the GM-CSF Gene in Four Patients with Stage IV Renal Cell Cancer in Japan : Clinical and Immunological Findings. (2004)
  • Author(s): K.Tani, M.Azuma, Y.Nakazaki, N.Oyaizu, H.Hase, J.Ohata, K.Takahashi, M.OiwaMonna, K.Hanazawa, Y.Wakumoto, K.Kawai, M.Noguchi, Y.Soda, R.Kunisaki, K.Watari, S.Takahashi, U.Machida, N.Satoh, A.Tojo, T.Maekawa, M.Eriguchi, S.Tomikawa, H.Tahara, Y.Inoue, H.Yoshikawa, Y.Yamada, A.Iwamoto, H.Hamada, N.Yamashita, K.Okumura, T.Kakizoe, H.Akaza, M.Fujime, S.C.Dale Ando, R.Mulligan, S.Asano
  • Journal Title: Mol.Therapy 10 Pages: 799-816
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibitory effect of low-dose estrogen on neointimal formation after balloon injury of rat carotid artery. (2004)
  • Author(s): Watanabe, T., Miyahara, Y., Akishita, M., Nakaoka, T., Yamashita, N., Iijima, K., Kim, H., Kozaki, K., Ouchi, Y.
  • Journal Title: Eur.J.Pharmacol. 502 Pages: 265-270
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Caveolin-1, Id3a and two LIM protein genes are upregulated by estrogen in vascular smooth muscle cells. (2004)
  • Author(s): Watanabe, T., Akishita, M., Nakaoka, T., He, H., Miyahara, Y., Yamashita, N., Wada, Y., Aburatani, H., Yoshizumi, M., Kozaki, K., Ouchi, Y.
  • Journal Title: Life Sci. 75 Pages: 1219-29
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A potential pro-angiogenic cell therapy with human placenta-derived mesenchymal cells. (2004)
  • Author(s): Nishishita, T., Ouchi, K., Zhang, X., Inoue, M., Inazawa, T., Yoshiura, K., Kuwabara, K., Nakaoka, T., Watanabe, N., Igura, K., Takahashi, T.A., Yamashita, N.
  • Journal Title: Biochem.Biophysic Res.Commun. 325 Pages: 24-31
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Thyroglobulin-pulsed human monocyte-derived dendritic cells induce CD4^+T cell activation (2004)
  • Author(s): Morishita M., Uchimaru K., et al.
  • Journal Title: International Journal of Molecular Medicine 13 Pages: 33-39