Optimization of the proliferation and persistency of CAR T cells derived from human induced pluripotent stem cells
The effectiveness of chimaeric antigen receptor (CAR) T-cell immunotherapies against solid tumours relies on the accumulation, proliferation and persistency of T cells at the tumour site. Here we show that the proliferation of CD8αβ cytotoxic CAR T cells in solid tumours can be enhanced by deriving...
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| Veröffentlicht in: | Nature biomedical engineering 2023-01, Vol.7 (1), p.24-37 |
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| creator | Ueda, Tatsuki Shiina, Sara Iriguchi, Shoichi Terakura, Seitaro Kawai, Yohei Kabai, Ryotaro Sakamoto, Satoko Watanabe, Akira Ohara, Kohei Wang, Bo Xu, Huaigeng Minagawa, Atsutaka Hotta, Akitsu Woltjen, Knut Uemura, Yasushi Kodama, Yuzo Seno, Hiroshi Nakatsura, Tetsuya Tamada, Koji Kaneko, Shin |
| description | The effectiveness of chimaeric antigen receptor (CAR) T-cell immunotherapies against solid tumours relies on the accumulation, proliferation and persistency of T cells at the tumour site. Here we show that the proliferation of CD8αβ cytotoxic CAR T cells in solid tumours can be enhanced by deriving and expanding them from a single human induced-pluripotent-stem-cell clone bearing a CAR selected for efficient differentiation. We also show that the proliferation and persistency of the effector cells in the tumours can be further enhanced by genetically knocking out diacylglycerol kinase, which inhibits antigen-receptor signalling, and by transducing the cells with genes encoding for membrane-bound interleukin-15 (IL-15) and its receptor subunit IL-15Rα. In multiple tumour-bearing animal models, the engineered hiPSC-derived CAR T cells led to therapeutic outcomes similar to those of primary CD8 T cells bearing the same CAR. The optimization of effector CAR T cells derived from pluripotent stem cells may aid the development of long-lasting antigen-specific T-cell immunotherapies for the treatment of solid tumours.
Cytotoxic CAR T cells derived from human induced pluripotent stem cells can be genetically engineered for enhanced proliferation and persistency in solid tumours. |
| doi_str_mv | 10.1038/s41551-022-00969-0 |
| format | Article |
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Cytotoxic CAR T cells derived from human induced pluripotent stem cells can be genetically engineered for enhanced proliferation and persistency in solid tumours.</description><identifier>ISSN: 2157-846X</identifier><identifier>EISSN: 2157-846X</identifier><identifier>DOI: 10.1038/s41551-022-00969-0</identifier><identifier>PMID: 36509913</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/100 ; 13/21 ; 13/31 ; 59/5 ; 631/61/2320 ; 631/67/1059/2325 ; Animal models ; Animals ; Antigens ; Biomedical and Life Sciences ; Biomedical Engineering/Biotechnology ; Biomedicine ; CD8 antigen ; CD8-Positive T-Lymphocytes ; Cell Proliferation ; Chimeric antigen receptors ; Cytotoxicity ; Diacylglycerol kinase ; Effector cells ; Genetic engineering ; Humans ; Immunotherapy ; Induced Pluripotent Stem Cells - pathology ; Interleukin 15 ; Kinases ; Lymphocytes ; Lymphocytes T ; Neoplasms - therapy ; Optimization ; Pluripotency ; Receptors ; Receptors, Antigen, T-Cell - genetics ; Solid tumors ; Stem cell transplantation ; Stem cells ; Tumors</subject><ispartof>Nature biomedical engineering, 2023-01, Vol.7 (1), p.24-37</ispartof><rights>The Author(s) 2022</rights><rights>2022. The Author(s).</rights><rights>The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c518t-99eeeee46dc074b33346cd3db06cd64305a21d03c029aef5dfc4c3af0fe0c19a3</citedby><cites>FETCH-LOGICAL-c518t-99eeeee46dc074b33346cd3db06cd64305a21d03c029aef5dfc4c3af0fe0c19a3</cites><orcidid>0000-0002-1194-8046 ; 0000-0003-2293-1183 ; 0000-0002-2619-7441 ; 0000-0003-2291-4586</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41551-022-00969-0$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41551-022-00969-0$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,777,781,882,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36509913$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ueda, Tatsuki</creatorcontrib><creatorcontrib>Shiina, Sara</creatorcontrib><creatorcontrib>Iriguchi, Shoichi</creatorcontrib><creatorcontrib>Terakura, Seitaro</creatorcontrib><creatorcontrib>Kawai, Yohei</creatorcontrib><creatorcontrib>Kabai, Ryotaro</creatorcontrib><creatorcontrib>Sakamoto, Satoko</creatorcontrib><creatorcontrib>Watanabe, Akira</creatorcontrib><creatorcontrib>Ohara, Kohei</creatorcontrib><creatorcontrib>Wang, Bo</creatorcontrib><creatorcontrib>Xu, Huaigeng</creatorcontrib><creatorcontrib>Minagawa, Atsutaka</creatorcontrib><creatorcontrib>Hotta, Akitsu</creatorcontrib><creatorcontrib>Woltjen, Knut</creatorcontrib><creatorcontrib>Uemura, Yasushi</creatorcontrib><creatorcontrib>Kodama, Yuzo</creatorcontrib><creatorcontrib>Seno, Hiroshi</creatorcontrib><creatorcontrib>Nakatsura, Tetsuya</creatorcontrib><creatorcontrib>Tamada, Koji</creatorcontrib><creatorcontrib>Kaneko, Shin</creatorcontrib><title>Optimization of the proliferation and persistency of CAR T cells derived from human induced pluripotent stem cells</title><title>Nature biomedical engineering</title><addtitle>Nat. Biomed. Eng</addtitle><addtitle>Nat Biomed Eng</addtitle><description>The effectiveness of chimaeric antigen receptor (CAR) T-cell immunotherapies against solid tumours relies on the accumulation, proliferation and persistency of T cells at the tumour site. Here we show that the proliferation of CD8αβ cytotoxic CAR T cells in solid tumours can be enhanced by deriving and expanding them from a single human induced-pluripotent-stem-cell clone bearing a CAR selected for efficient differentiation. We also show that the proliferation and persistency of the effector cells in the tumours can be further enhanced by genetically knocking out diacylglycerol kinase, which inhibits antigen-receptor signalling, and by transducing the cells with genes encoding for membrane-bound interleukin-15 (IL-15) and its receptor subunit IL-15Rα. In multiple tumour-bearing animal models, the engineered hiPSC-derived CAR T cells led to therapeutic outcomes similar to those of primary CD8 T cells bearing the same CAR. The optimization of effector CAR T cells derived from pluripotent stem cells may aid the development of long-lasting antigen-specific T-cell immunotherapies for the treatment of solid tumours.
Cytotoxic CAR T cells derived from human induced pluripotent stem cells can be genetically engineered for enhanced proliferation and persistency in solid tumours.</description><subject>13/100</subject><subject>13/21</subject><subject>13/31</subject><subject>59/5</subject><subject>631/61/2320</subject><subject>631/67/1059/2325</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antigens</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>Biomedicine</subject><subject>CD8 antigen</subject><subject>CD8-Positive T-Lymphocytes</subject><subject>Cell Proliferation</subject><subject>Chimeric antigen receptors</subject><subject>Cytotoxicity</subject><subject>Diacylglycerol kinase</subject><subject>Effector cells</subject><subject>Genetic engineering</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Induced Pluripotent Stem Cells - pathology</subject><subject>Interleukin 15</subject><subject>Kinases</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Neoplasms - 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Biomed. Eng</stitle><addtitle>Nat Biomed Eng</addtitle><date>2023-01-01</date><risdate>2023</risdate><volume>7</volume><issue>1</issue><spage>24</spage><epage>37</epage><pages>24-37</pages><issn>2157-846X</issn><eissn>2157-846X</eissn><abstract>The effectiveness of chimaeric antigen receptor (CAR) T-cell immunotherapies against solid tumours relies on the accumulation, proliferation and persistency of T cells at the tumour site. Here we show that the proliferation of CD8αβ cytotoxic CAR T cells in solid tumours can be enhanced by deriving and expanding them from a single human induced-pluripotent-stem-cell clone bearing a CAR selected for efficient differentiation. We also show that the proliferation and persistency of the effector cells in the tumours can be further enhanced by genetically knocking out diacylglycerol kinase, which inhibits antigen-receptor signalling, and by transducing the cells with genes encoding for membrane-bound interleukin-15 (IL-15) and its receptor subunit IL-15Rα. In multiple tumour-bearing animal models, the engineered hiPSC-derived CAR T cells led to therapeutic outcomes similar to those of primary CD8 T cells bearing the same CAR. The optimization of effector CAR T cells derived from pluripotent stem cells may aid the development of long-lasting antigen-specific T-cell immunotherapies for the treatment of solid tumours.
Cytotoxic CAR T cells derived from human induced pluripotent stem cells can be genetically engineered for enhanced proliferation and persistency in solid tumours.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>36509913</pmid><doi>10.1038/s41551-022-00969-0</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-1194-8046</orcidid><orcidid>https://orcid.org/0000-0003-2293-1183</orcidid><orcidid>https://orcid.org/0000-0002-2619-7441</orcidid><orcidid>https://orcid.org/0000-0003-2291-4586</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/100 13/21 13/31 59/5 631/61/2320 631/67/1059/2325 Animal models Animals Antigens Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine CD8 antigen CD8-Positive T-Lymphocytes Cell Proliferation Chimeric antigen receptors Cytotoxicity Diacylglycerol kinase Effector cells Genetic engineering Humans Immunotherapy Induced Pluripotent Stem Cells - pathology Interleukin 15 Kinases Lymphocytes Lymphocytes T Neoplasms - therapy Optimization Pluripotency Receptors Receptors, Antigen, T-Cell - genetics Solid tumors Stem cell transplantation Stem cells Tumors |
| title | Optimization of the proliferation and persistency of CAR T cells derived from human induced pluripotent stem cells |
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