Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells
Abstract The integration of molecular targeted therapeutics with chimeric antigen receptor T (CAR-T) cell therapy represents a novel strategy to amplify the anti-tumor efficacy of immunotherapy. While CD19-targeted CAR-T cells and Janus kinase (JAK) inhibitors have independently shown efficacy again...
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| Format: | Article |
| Language: | English |
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Springer
2025-02-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-024-03927-8 |
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| author | Kohei Mitsuno Masaya Suematsu Yuki Naito Azusa Mayumi Hideki Yoshida Shinya Osone Toshihiko Imamura Yozo Nakazawa Shigeki Yagyu Tomoko Iehara |
| author_facet | Kohei Mitsuno Masaya Suematsu Yuki Naito Azusa Mayumi Hideki Yoshida Shinya Osone Toshihiko Imamura Yozo Nakazawa Shigeki Yagyu Tomoko Iehara |
| author_sort | Kohei Mitsuno |
| collection | DOAJ |
| description | Abstract The integration of molecular targeted therapeutics with chimeric antigen receptor T (CAR-T) cell therapy represents a novel strategy to amplify the anti-tumor efficacy of immunotherapy. While CD19-targeted CAR-T cells and Janus kinase (JAK) inhibitors have independently shown efficacy against certain B-cell leukemias, such as Philadelphia chromosome-like acute lymphoblastic leukemia, the concurrent use of JAK1/2 inhibitors, such as ruxolitinib, has been implicated in reducing CAR-T cell potency by inhibiting the JAK1-dependent T cell activation pathway. This study explores the combinatorial use of a selective type II JAK2 inhibitor, CHZ868, with CD19 CAR-T cells, revealing a synergistic enhancement of anti-leukemic activity across B-cell tumor models irrespective of JAK2 mutational status. CHZ868-mediated JAK2 inhibition did not induce the exhaustion of CAR-T cells, maintaining efficacy over repeated tumor challenges and significantly extending survival in mouse models engrafted with JAK2 inhibitor-resistant leukemia cells (median survival, CD19 CAR-T + CHZ868 vs. CD19 CAR-T + DMSO: 32 days vs. 26 days, p = 0.0303). Transcriptomic analyses suggest that CHZ868 impedes CAR-T cell differentiation while preserving their proliferative capacity, a crucial factor in maintaining CAR-T cell functionality. Therefore, the selective inhibition of the JAK2 pathway may potentiate CAR-T cell therapy and offer a viable treatment strategy for patients with resistant B-cell leukemias. |
| format | Article |
| id | doaj-art-233b96f248054e73aeede449c9a5c841 |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-233b96f248054e73aeede449c9a5c8412025-02-02T12:26:26ZengSpringerCancer Immunology, Immunotherapy1432-08512025-02-0174311410.1007/s00262-024-03927-8Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cellsKohei Mitsuno0Masaya Suematsu1Yuki Naito2Azusa Mayumi3Hideki Yoshida4Shinya Osone5Toshihiko Imamura6Yozo Nakazawa7Shigeki Yagyu8Tomoko Iehara9Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pediatrics, Shinshu University School of MedicineDepartment of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of MedicineAbstract The integration of molecular targeted therapeutics with chimeric antigen receptor T (CAR-T) cell therapy represents a novel strategy to amplify the anti-tumor efficacy of immunotherapy. While CD19-targeted CAR-T cells and Janus kinase (JAK) inhibitors have independently shown efficacy against certain B-cell leukemias, such as Philadelphia chromosome-like acute lymphoblastic leukemia, the concurrent use of JAK1/2 inhibitors, such as ruxolitinib, has been implicated in reducing CAR-T cell potency by inhibiting the JAK1-dependent T cell activation pathway. This study explores the combinatorial use of a selective type II JAK2 inhibitor, CHZ868, with CD19 CAR-T cells, revealing a synergistic enhancement of anti-leukemic activity across B-cell tumor models irrespective of JAK2 mutational status. CHZ868-mediated JAK2 inhibition did not induce the exhaustion of CAR-T cells, maintaining efficacy over repeated tumor challenges and significantly extending survival in mouse models engrafted with JAK2 inhibitor-resistant leukemia cells (median survival, CD19 CAR-T + CHZ868 vs. CD19 CAR-T + DMSO: 32 days vs. 26 days, p = 0.0303). Transcriptomic analyses suggest that CHZ868 impedes CAR-T cell differentiation while preserving their proliferative capacity, a crucial factor in maintaining CAR-T cell functionality. Therefore, the selective inhibition of the JAK2 pathway may potentiate CAR-T cell therapy and offer a viable treatment strategy for patients with resistant B-cell leukemias.https://doi.org/10.1007/s00262-024-03927-8CAR-T cell therapyJAK2 inhibitorMemory T cell fractionPh-like ALL |
| spellingShingle | Kohei Mitsuno Masaya Suematsu Yuki Naito Azusa Mayumi Hideki Yoshida Shinya Osone Toshihiko Imamura Yozo Nakazawa Shigeki Yagyu Tomoko Iehara Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells Cancer Immunology, Immunotherapy CAR-T cell therapy JAK2 inhibitor Memory T cell fraction Ph-like ALL |
| title | Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells |
| title_full | Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells |
| title_fullStr | Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells |
| title_full_unstemmed | Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells |
| title_short | Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells |
| title_sort | selective jak2 pathway inhibition enhances anti leukemic functionality in cd19 car t cells |
| topic | CAR-T cell therapy JAK2 inhibitor Memory T cell fraction Ph-like ALL |
| url | https://doi.org/10.1007/s00262-024-03927-8 |
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