Development of gene therapy for refractory non-Hodgkin lymphoma using T-cells expressing a chimeric antigen receptor
Project/Area Number |
24390247
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Partial Multi-year Fund |
Section | 一般 |
Research Field |
Hematology
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Research Institution | Jichi Medical University |
Principal Investigator |
OZAWA keiya 自治医科大学, 医学部, 客員教授 (30137707)
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Co-Investigator(Kenkyū-buntansha) |
TSUKAHARA Tomonori 自治医科大学, 医学部, 講師 (10362120)
UCHIBORI Ryousuke 自治医科大学, 医学部, 助教 (20458285)
OHMINE Ken 自治医科大学, 医学部, 講師 (90316521)
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Project Period (FY) |
2012-04-01 – 2015-03-31
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Project Status |
Completed (Fiscal Year 2014)
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Budget Amount *help |
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2013: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2012: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
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Keywords | 遺伝子治療 / 免疫療法 / 細胞療法 / キメラ抗原受容体 / Tリンパ球 / 造血器腫瘍 / 血液腫瘍学 |
Outline of Final Research Achievements |
Gene therapy for refractory B-cell non-Hodgkin lymphoma using T-cells expressing a chimeric antigen receptor (CAR) was studied as follows: (1) To improve the anti-tumor activity, T-cells were transduced with CD19-targeted CAR and IL-21 genes. However, the therapeutic effect was not enhanced by IL-21 in tumor-bearing mice. (2) For the safety, we developed a switch promoter, which stimulates transgene expression in CAR T-cells upon interaction with target cells. We demonstrated that this system works through CAR-dependent signaling in CAR T-cells in vitro and in tumor-bearing mice. (3) We manufactured CD19-CAR T-cells from patient-derived PBMCs by a closed cell-processing system, and confirmed that these T-cells can kill B lymphoma cells in vitro. (4) A clinical protocol (CD19-CAR T-cell therapy for B-cell lymphoma) was approved by IRB and the Ministry of Health, Labour and Welfare. Enrollment started in December 2014.
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Report
(4 results)
Research Products
(51 results)
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[Journal Article] Comparative analyses of adeno-associated viral vector serotypes 1, 2, 5, 8 and 9 in marmoset, mouse and macaque cerebral cortex.2015
Author(s)
Watakabe A, Ohtsuka M, Kinoshita M, Takaji M, Isa K, Mizukami H, Ozawa K, Isa T, and Yamamori T.
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Journal Title
Neurosci. Res.
Volume: 93
Pages: 144-157
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The Tol2 transposon system mediates the genetic engineering of T-cells with CD19-specific chimeric antigen receptors for B-cell malignancies2015
Author(s)
Tsukahara, T., Iwase, N., Kawakami, K., Iwasaki, M., Yamamoto, C., Ohmine, K., Uchibori, R., Teruya, T., Ido, H., Saga, Y., Urabe, M., Mizukami, H., Kume, A., Nakamura, M., Brentjens, R., and Ozawa, K.
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Journal Title
Gene Therapy
Volume: 22
Issue: 2
Pages: 209-215
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Long-term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group.2015
Author(s)
Hirokawa M, Sawada K, Fujishima N, Teramura M, Bessho M, Dan K, Tsurumi H, Nakao S, Urabe A, Fujisawa S, Yonemura Y, Kawano F, Oshimi K, Sugimoto K, Matsuda A, Karasawa M, Arai A, Komatsu N, Harigae H, Omine M, Ozawa K, Kurokawa M; PRCA Collaborative Study Group.
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Journal Title
Br J Haematol.
Volume: in press
Issue: 6
Pages: 879-886
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Novel anti-tumor mechanism of galanin receptor type 2 in head and neck squamous cell carcinoma cells2014
Author(s)
Uehara T, Kanazawa T, Mizukami H, Uchibori R, Tsukahara T, Urabe M, Kume A, Misawa K, Carey T, Suzuki M, Ichimura K, Ozawa K
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Journal Title
Cancer Science
Volume: 105
Issue: 1
Pages: 72-80
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The prevalence of neutralizing antibodies against adeno-associated virus capsids is reduced in young Japanese individuals.2014
Author(s)
Mimuro J, Mizukami H, Shima M, Matsushita T, Taki M, Muto S, Higasa S, Sakai M, Ohmori T, Madoiwa S, Ozawa K, and Sakata Y.
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Journal Title
J. Med. Virol.
Volume: 86
Issue: 11
Pages: 1990-1997
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] IL-21 is not necessary for anti-lymphoma effects of T cells expressing second-generation CD19-specific chimeric antigen receptors in a xenograft mouse model.2014
Author(s)
Yamamoto C, Tsukahara T, Omine K, Teruya T, Ido H, Uchibori R, Urabe M, Mizukami H, Kume A, Nakamura M, Ozawa K.
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Journal Title
Jichi Medical University Journal
Volume: 36
Pages: 23-31
NAID
Related Report
Peer Reviewed
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[Journal Article] CD19 target-engineered T-cells accumulate at tumor lesions in human B-cell lymphoma xenograft mouse models2013
Author(s)
Tsukahara T, Ohmine K, Yamamoto C, Uchibori R, Ido H, Teruya T, Urabe M, Mizukami H, Kume A, Nakamura M, Mineno J, Takesako K, Riviere I, Sadelain M, Brentjens R, Ozawa K
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Journal Title
Biochemical and Biophysical Research Communications
Volume: 438
Issue: 1
Pages: 84-89
DOI
Related Report
Peer Reviewed
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[Journal Article] Unrelated allogeneic bone marrow-derived mesenchymal stem cells for steroid-refractory acute graft-versus-host disease: a phase I/II study.2013
Author(s)
Muroi K, Miyamura K, Ohashi K, Murata M, Eto T, Kobayashi N, Taniguchi S, Imamura M, Ando K, Kato S, Mori T, Teshima T, Mori M, Ozawa K.
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Journal Title
Int J Hematol.
Volume: 98
Issue: 2
Pages: 206-213
DOI
NAID
Related Report
Peer Reviewed
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[Journal Article] Minimizing the inhibitory effect of neutralizing antibody for efficient gene expression in the liver with adeno-associated virus 8 vectors.2013
Author(s)
Mimuro J, Mizukami H, Hishikawa S, Ikemoto T, Ishiwata A, Sakata A, Ohmori T, Madoiwa S, Ono F, Ozawa K, and Sakata Y
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Journal Title
Mol Ther
Volume: 21
Issue: 2
Pages: 318-323
DOI
Related Report
Peer Reviewed
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[Journal Article] Interleukin-10 expression induced by adeno-associated virus vector suppresses proteinuria in Zucker obese rats2012
Author(s)
Ogura M, Urabe M, Akimoto T, Onishi A, Ito C, Ito T, Tsukahara T, Mizukami H, Kume A, Muto S, Kusano E, and Ozawa K.
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Journal Title
Gene Ther
Volume: 19巻
Issue: 5
Pages: 476-82
DOI
Related Report
Peer Reviewed
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[Journal Article] Recovery of neurogenic amines in phenylketonuria mice after liver-targeted gene therapy2012
Author(s)
Yagi, H., Sanechika, S., Ichinose, H., Sumi-Ichinose, C., Mizukami, H., Urabe, M., Ozawa, K., and Kume, A.
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Journal Title
Neuroreport
Volume: 23
Issue: 1
Pages: 30-34
DOI
Related Report
Peer Reviewed
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[Presentation] Tol2 transposon-based gene transfer of CD19-specific chimeric antigen receptors into human T-cells.2014
Author(s)
Tsukahara T, Iwase N, Yamamoto C, Ohmine K, Uchibori R, Teruya T, Ido H, Urabe M, Mizukami H, Kume A, Nakamura M, Brentjens R, Kawakami K and Ozawa K.
Organizer
第76回日本血液学会学術集会
Place of Presentation
大阪
Year and Date
2014-11-02
Related Report
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[Presentation] Activation signals from CAR permit NFAT-controlled inducible expression of transgenes in PBMCs.2014
Author(s)
Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Riviere I, Sadelain M, Brentjens RJ, Mineno J, Ozawa K.
Organizer
第76回日本血液学会学術集会
Place of Presentation
大阪
Year and Date
2014-11-02
Related Report
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[Presentation] Activation signals from chimeric antigen receptors permit NFAT-controlled inducible expression of transgene in PBMCs.2014
Author(s)
Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Mineno J, Ozawa K.
Organizer
第73回日本癌学会学術総会
Place of Presentation
横浜
Year and Date
2014-09-26
Related Report
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[Presentation] Tol2 transposon-mediated gene transfer of CD19-CAR to primary human T-cells for the treatment of B-cell malignancies.2014
Author(s)
Tsukahara T, Iwase N, Yamamoto C, Ohmine K, Uchibori R, Takeshi T, Urabe M, Mizukami H, Kume A, Nakamura M, Brentjens R J, Kawakami K, Ozawa K.
Organizer
第20回日本遺伝子治療学会
Place of Presentation
東京
Year and Date
2014-08-08
Related Report
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[Presentation] The NFAT response elements in the IL-2 gene promoter permit visualization and quantification of activation status in CAR-expressing PBMCs.2014
Author(s)
Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Riviere I, Sadelain M, Brentjens RJ, Mineno J, Ozawa K.
Organizer
第20回日本遺伝子治療学会
Place of Presentation
東京
Year and Date
2014-08-08
Related Report
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[Presentation] Development of switch promoters that is activated to induce exogenous gene expression upon the recognition of CD19 by chimeric antigen receptors.2014
Author(s)
Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Riviere I, Sadelain M, Brentjens RJ, Mineno J, Ozawa K.
Organizer
17th Annual Meeting of the American Society of Gene & Cell Therapy.
Place of Presentation
Washington, D.C.
Year and Date
2014-05-22
Related Report
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[Presentation] Tumor targeting and anti-tumor activity mediated by T-lymphocytes with an anti-CD19 CAR in human B-cell lymphoma models.
Author(s)
Tsukahara T, Ohmine K, Uchibori R, Ido H, Urabe M, Mizukami H, Kume A, Nakamura M, Riviere I, Sadelain M, Brentjens R, Ozawa K.
Organizer
第18回日本遺伝子治療学会
Place of Presentation
岡山市
Related Report
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[Presentation] Tumor targeting using T-lymphocytes with an anti-CD19 chimeric antigen receptor for B cell lymphoma.
Author(s)
Tsukahara T, Ohmine K, Uchibori R, Ido H, Urabe M, Mizukami H, Kume A, Nakamura M, Riviere I, Sadelain M, Brentjens R, Ozawa K.
Organizer
第75回日本血液学会学術集会
Place of Presentation
札幌市
Related Report
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[Presentation] DEVELOPMENT OF SIN RETROVIRAL VECTORS EQUIPPED WITH SWITCH PROMOTERS DRIVEN BY ACTIVATION SIGNALS FROM THE CHIMERIC ANTIGEN RECEPTORS.
Author(s)
Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Riviere I, Sadelain M, Brentjens RJ, Mineno J, Ozawa K.
Organizer
第18回日本遺伝子治療学会
Place of Presentation
岡山市
Related Report
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[Presentation] Development of switch promoters that would respond to activation signals from the chimeric antigen receptors.
Author(s)
Uchibori R, Ninomiya S, Tsukahara T, Ido H, Teruya T, Ohmine K, Urabe M, Mizukami H, Kume A, Riviere I, Sadelain M, Brentjens RJ, Mineno J, Ozawa K.
Organizer
第72回日本癌学会学術総会
Place of Presentation
横浜市
Related Report
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