Development of immunogene therapy using T-cells expressing a chimeric antigen receptor for adult T-cell leukemia

• Project/Area Number: 25430155
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Jichi Medical University
• Principal Investigator: Tsukahara Tomonori 自治医科大学, 医学部, 講師 (10362120)
• Co-Investigator(Kenkyū-buntansha): OHMINE Ken 自治医科大学, 医学部, 講師 (90316521)
• Co-Investigator(Renkei-kenkyūsha): MORISHITA Kazuhiro 宮崎大学, 医学部, 教授 (80260321)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 免疫遺伝子療法 / キメラ抗原受容体 / T細胞 / 造血器腫瘍 / 遺伝子治療 / 成人T細胞白血病 / 免疫療法 / T細胞療法

Outline of Final Research Achievements

We conducted experiments to develop immunogene therapy using T-cells expressing a chimeric antigen receptor (CAR) for the treatment of refractory adult T-cell leukemia (ATL). For targeting ATL cells, CARs consisting of an anti-CADM1 antibody or an anti-CD30 antibody, fused to CD28 and CD3ζ signal domains, were constructed. Normal peripheral blood mononuclear cells were transduced with retroviral vectors containing CARs. CD30-CAR-transduced T-cells were expanded ex vivo, and efficiently lyzed CD30(+) ATL cells lines but not a CD30(-) B-cell line in vitro. These results indicate that CD30-CAR T-cells could be useful in the treatment of ATL.

Research Products

• [Journal Article] 遺伝子操作Tリンパ球を用いた癌遺伝子治療 (2015)
  • Author(s): 塚原智典
  • Journal Title: Pharma Medica Volume: 33 Pages: 41-45
• [Journal Article] The Tol2 transposon system mediates the genetic engineering of T-cells with CD19-specific chimeric antigen receptors for B-cell malignancies (2015)
  • 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.
  • Journal Title: Gene Therapy Volume: 22 Issue: 2 Pages: 209-215
  • DOI: 10.1038/gt.2014.104
  • Peer Reviewed / Open Access
• [Journal Article] Cancer gene therapy using mesenchymal stem cells. (2014)
  • Author(s): Uchibori R, Tsukahara T, Ohmine K, Ozawa K.
  • Journal Title: Int J Hematol. Volume: 99 Issue: 4 Pages: 377-82
  • DOI: 10.1007/s12185-014-1537-7
  • Peer Reviewed
• [Journal Article] L-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, Ohmine K, Teruya T, Ido H, Uchibori R, Urabe M, Mizukami H, Kume A, Nakamura M, Ozawa K.
  • Journal Title: Jichi Medical University Journal Volume: 36 Pages: 23-31
  • Peer Reviewed
• [Journal Article] Novel anti-tumor mechanism of galanin receptor type 2 in head and neck squamous cell carcinoma cells (2014)
  • 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
  • Journal Title: Cancer Science Volume: 105 Issue: 1 Pages: 72-80
  • DOI: 10.1111/cas.12315
  • Peer Reviewed / Open Access
• [Journal Article] CD19 target-engineered T-cells accumulate at tumor lesions in human B-cell lymphoma xenograft mouse models (2013)
  • 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
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 438 Issue: 1 Pages: 84-89
  • DOI: 10.1016/j.bbrc.2013.07.030
  • Peer Reviewed
• [Journal Article] NF-κB activity regulates mesenchymal stem cell accumulation at tumor sites. (2013)
  • Author(s): Uchibori R, Tsukahara T, Mizuguchi H, Saga Y, Urabe M, Mizukami H, Kume A, Ozawa K
  • Journal Title: Cancer Research Volume: 73 Issue: 1 Pages: 364-372
  • DOI: 10.1158/0008-5472.can-12-0088
  • Peer Reviewed
• [Presentation] CD19特異的キメラ抗原受容体(CAR)発現T細胞を用いた養子免疫療法の臨床開発 (2015)
  • Author(s): 大嶺 謙
  • Organizer: 第7回血液疾患免疫療法研究会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-09-26
  • Invited
• [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
• [Presentation] Generation of T-cells expressing a CD19-specific CAR by the Tol2 transposon system. (2014)
  • Author(s): Tsukahara T, Ohmine K, Uchibori R, Urabe M, Mizukami H, Kume A, Nakamura M, Ozawa K.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [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
• [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日本遺伝子治療学会
  • Place of Presentation: 岡山
• [Presentation] Anti-tumor activity of CD19-specific chimeric antigen receptor-modified T-cells for B cell lymphoma.
  • Author(s): Tsukahara T, Ohmine K, Uchibori R, Ido H, Urabe M, Mizukami H, Kume A, Nakamura M, Ozawa K.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [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