Download pdf
Challenges and innovations in managing cytokine release syndrome in CAR-T therapy: mechanisms, clinical impact, and future directions
- 1 University of Toronto
* Author to whom correspondence should be addressed.
Abstract
Chimeric Antigen Receptor (CAR) T-cell treatment represents a groundbreaking advancement in cancer immunotherapy, particularly for blood-related cancers. Nevertheless, its therapeutic application is sometimes hindered by Cytokine Release Syndrome (CRS), an inflammatory response that has the potential to be life-threatening. This review explores the underlying causes of CRS, its clinical symptoms, and the difficulties encountered in treating affected people. In addition, we investigate contemporary treatment methods, such as administering tocilizumab and utilizing kinase inhibitors and CAR-NK cells, to mitigate the severity of CRS while maintaining the effectiveness of CAR-T cell therapy. In addition, we emphasize upcoming advancements in CAR-T technology, including reversible and irreversible CAR switches, which are intended to improve both safety and therapeutic results. This study emphasizes the continuous requirement for research to enhance CAR-T cell treatment by finding a middle ground between optimizing its effectiveness and guaranteeing patient safety.
Keywords
Cancer, Immunotherapy, CAR-T cell therapy, Cytokine release syndrome, CAR-NK cell
[1]. Ribas, A., & Wolchok, J. D. (2018). Cancer Immunotherapy Using Checkpoint Blockade. Science (New York, N.Y.), 359(6382), 1350–1355. https://doi.org/10.1126/science.aar4060
[2]. June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S., & Milone, M. C. (2018). CAR T cell immunotherapy for human cancer. Science, 359(6382), 1361–1365. https://doi.org/10.1126/science.aar6711
[3]. Akhoundi, M., Mohammadi, M., Sahraei, S. S., Sheykhhasan, M., & Fayazi, N. (2021). CAR T cell therapy as a promising approach in cancer immunotherapy: Challenges and opportunities. Cellular Oncology, 44(3), 495–523. https://doi.org/10.1007/s13402-021-00593-1
[4]. Lipowska-Bhalla, G., Gilham, D. E., Hawkins, R. E., & Rothwell, D. G. (2012). Targeted immunotherapy of cancer with CAR T cells: Achievements and challenges. Cancer Immunology, Immunotherapy: CII, 61(7), 953–962. https://doi.org/10.1007/s00262-012-1254-0
[5]. Kuwana, Y., Asakura, Y., Utsunomiya, N., Nakanishi, M., Arata, Y., Itoh, S., Nagase, F., & Kurosawa, Y. (1987). Expression of chimeric receptor composed of immunoglobulin-derived V resions and T-cell receptor-derived C regions. Biochemical and Biophysical Research Communications, 149(3), 960–968. https://doi.org/10.1016/0006-291X(87)90502-X
[6]. Gross, G., Waks, T., & Eshhar, Z. (1989). Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proceedings of the National Academy of Sciences of the United States of America, 86(24), 10024–10028.
[7]. Chmielewski, M., Kopecky, C., Hombach, A. A., & Abken, H. (2011). IL-12 Release by Engineered T Cells Expressing Chimeric Antigen Receptors Can Effectively Muster an Antigen-Independent Macrophage Response on Tumor Cells That Have Shut Down Tumor Antigen Expression. Cancer Research, 71(17), 5697–5706. https://doi.org/10.1158/0008-5472.CAN-11-0103
[8]. Huang, J., Huang, X., & Huang, J. (2022). CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies. Frontiers in Immunology, 13, 1019115. https://doi.org/10.3389/fimmu.2022.1019115
[9]. Sterner, R. C., & Sterner, R. M. (2021). CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer Journal, 11(4), Article 4. https://doi.org/10.1038/s41408-021-00459-7
[10]. Frey, N. V., & Porter, D. L. (2016). Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. Hematology: The American Society of Hematology Education Program, 2016(1), 567–572.
[11]. Sadelain, M., Brentjens, R., & Riviere, I. (2013). The basic principles of chimeric antigen receptor (CAR) design. Cancer Discovery, 3(4), 388–398. https://doi.org/10.1158/2159-8290.CD-12-0548
[12]. Frey, N., & Porter, D. (2019). Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy. Biology of Blood and Marrow Transplantation, 25(4), e123–e127. https://doi.org/10.1016/j.bbmt.2018.12.756
[13]. Hay, K. A., Hanafi, L.-A., Li, D., Gust, J., Liles, W. C., Wurfel, M. M., López, J. A., Chen, J., Chung, D., Harju-Baker, S., Cherian, S., Chen, X., Riddell, S. R., Maloney, D. G., & Turtle, C. J. (2017). Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor–modified T-cell therapy. Blood, 130(21), 2295–2306. https://doi.org/10.1182/blood-2017-06-793141
[14]. Teachey, D. T., Lacey, S. F., Shaw, P. A., Melenhorst, J. J., Maude, S. L., Frey, N., Pequignot, E., Gonzalez, V. E., Chen, F., Finklestein, J., Barrett, D. M., Weiss, S. L., Fitzgerald, J. C., Berg, R. A., Aplenc, R., Callahan, C., Rheingold, S. R., Zheng, Z., Rose-John, S., … Grupp, S. A. (2016). Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discovery, 6(6), 664–679. https://doi.org/10.1158/2159-8290.CD-16-0040
[15]. Freyer, C. W., & Porter, D. L. (2020). Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies. Journal of Allergy and Clinical Immunology, 146(5), 940–948. https://doi.org/10.1016/j.jaci.2020.07.025
[16]. Morris, E. C., Neelapu, S. S., Giavridis, T., & Sadelain, M. (2022). Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nature Reviews. Immunology, 22(2), 85–96. https://doi.org/10.1038/s41577-021-00547-6
[17]. Lee, D. W., Gardner, R., Porter, D. L., Louis, C. U., Ahmed, N., Jensen, M., Grupp, S. A., & Mackall, C. L. (2014). Current concepts in the diagnosis and management of cytokine release syndrome. Blood, 124(2), 188–195. https://doi.org/10.1182/blood-2014-05-552729
[18]. Hay, K. A. (n.d.). Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor‐modified (CAR‐) T cell therapy. https://doi.org/10.1111/bjh.15644
[19]. Jiang, H., Liu, L., Guo, T., Wu, Y., Ai, L., Deng, J., Dong, J., Mei, H., & Hu, Y. (2019). Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy. Annals of Hematology, 98(7), 1721–1732. https://doi.org/10.1007/s00277-019-03685-z
[20]. Porter, D., Frey, N., Wood, P. A., Weng, Y., & Grupp, S. A. (2018). Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. Journal of Hematology & Oncology, 11, 35. https://doi.org/10.1186/s13045-018-0571-y
[21]. Lee, D. W., Santomasso, B. D., Locke, F. L., Ghobadi, A., Turtle, C. J., Brudno, J. N., Maus, M. V., Park, J. H., Mead, E., Pavletic, S., Go, W. Y., Eldjerou, L., Gardner, R. A., Frey, N., Curran, K. J., Peggs, K., Pasquini, M., DiPersio, J. F., Brink, M. R. M. van den, … Neelapu, S. S. (2019). ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biology of Blood and Marrow Transplantation, 25(4), 625–638. https://doi.org/10.1016/j.bbmt.2018.12.758
[22]. Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M., Stemmler, H. J., Schlößer, H. A., Schlaak, M., Kochanek, M., Böll, B., & von Bergwelt-Baildon, M. S. (2018). Cytokine release syndrome. Journal for Immunotherapy of Cancer, 6, 56. https://doi.org/10.1186/s40425-018-0343-9
[23]. Zhang, Y., Qin, D., Shou, A. C., Liu, Y., Wang, Y., & Zhou, L. (2023). Exploring CAR-T Cell Therapy Side Effects: Mechanisms and Management Strategies. Journal of Clinical Medicine, 12(19), 6124. https://doi.org/10.3390/jcm12196124
[24]. Canna, S. W., & Marsh, R. A. (2020). Pediatric hemophagocytic lymphohistiocytosis. Blood, 135(16), 1332–1343. https://doi.org/10.1182/blood.2019000936
[25]. Bhaskar, S. T., Patel, V. G., Porter, D. L., Schuster, S. J., Nastoupil, L. J., Perales, M.-A., Tomas, A. A., Bishop, M. R., McGuirk, J. P., Maziarz, R. T., Chen, A. I., Bachanova, V., Maakaron, J. E., Riedell, P. A., & Oluwole, O. O. (2023). Chimeric antigen receptor T-cell therapy yields similar outcomes in patients with and without cytokine release syndrome. Blood Advances, 7(17), 4765–4772. https://doi.org/10.1182/bloodadvances.2022008937
[26]. Howard, S. C., Jones, D. P., & Pui, C.-H. (2011). The Tumor Lysis Syndrome. The New England Journal of Medicine, 364(19), 1844–1854. https://doi.org/10.1056/NEJMra0904569
[27]. Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G. R., Chiche, J.-D., Coopersmith, C. M., Hotchkiss, R. S., Levy, M. M., Marshall, J. C., Martin, G. S., Opal, S. M., Rubenfeld, G. D., van der Poll, T., Vincent, J.-L., & Angus, D. C. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315(8), 801–810. https://doi.org/10.1001/jama.2016.0287
[28]. Kotch, C., Barrett, D., & Teachey, D. T. (2019). Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome. Expert Review of Clinical Immunology, 15(8), 813–822. https://doi.org/10.1080/1744666X.2019.1629904
[29]. Le, R. Q., Li, L., Yuan, W., Shord, S. S., Nie, L., Habtemariam, B. A., Przepiorka, D., Farrell, A. T., & Pazdur, R. (2018). FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome. The Oncologist, 23(8), 943–947. https://doi.org/10.1634/theoncologist.2018-0028
[30]. Teachey, D. T., Rheingold, S. R., Maude, S. L., Zugmaier, G., Barrett, D. M., Seif, A. E., Nichols, K. E., Suppa, E. K., Kalos, M., Berg, R. A., Fitzgerald, J. C., Aplenc, R., Gore, L., & Grupp, S. A. (2013). Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood, 121(26), 5154–5157. https://doi.org/10.1182/blood-2013-02-485623
[31]. Mestermann, K., Giavridis, T., Weber, J., Rydzek, J., Frenz, S., Nerreter, T., Mades, A., Sadelain, M., Einsele, H., & Hudecek, M. (2019). The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR-T cells. Science Translational Medicine, 11(499), eaau5907. https://doi.org/10.1126/scitranslmed.aau5907
[32]. Sun, C., Shou, P., Du, H., Hirabayashi, K., Chen, Y., Herring, L. E., Ahn, S., Xu, Y., Suzuki, K., Li, G., Tsahouridis, O., Su, L., Savoldo, B., & Dotti, G. (2020). THEMIS-SHP1 Recruitment by 4–1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells. Cancer Cell, 37(2), 216-225.e6. https://doi.org/10.1016/j.ccell.2019.12.014
[33]. Ying, Z., Huang, X. F., Xiang, X., Liu, Y., Kang, X., Song, Y., Guo, X., Liu, H., Ding, N., Zhang, T., Duan, P., Lin, Y., Zheng, W., Wang, X., Lin, N., Tu, M., Xie, Y., Zhang, C., Liu, W., … Chen, S.-Y. (2019). A safe and potent anti-CD19 CAR T cell therapy. Nature Medicine, 25(6), 947–953. https://doi.org/10.1038/s41591-019-0421-7
[34]. Xiao, X., Huang, S., Chen, S., Wang, Y., Sun, Q., Xu, X., & Li, Y. (2021). Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies. Journal of Experimental & Clinical Cancer Research, 40(1), 367. https://doi.org/10.1186/s13046-021-02148-6
[35]. Jan, M., Scarfò, I., Larson, R. C., Walker, A., Schmidts, A., Guirguis, A. A., Gasser, J. A., Słabicki, M., Bouffard, A. A., Castano, A. P., Kann, M. C., Cabral, M. L., Tepper, A., Grinshpun, D. E., Sperling, A. S., Kyung, T., Sievers, Q., Birnbaum, M. E., Maus, M. V., & Ebert, B. L. (2021). Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide. Science Translational Medicine, 13(575), eabb6295. https://doi.org/10.1126/scitranslmed.abb6295
[36]. Juillerat, A., Tkach, D., Busser, B. W., Temburni, S., Valton, J., Duclert, A., Poirot, L., Depil, S., & Duchateau, P. (2019). Modulation of chimeric antigen receptor surface expression by a small molecule switch. BMC Biotechnology, 19, 44. https://doi.org/10.1186/s12896-019-0537-3
[37]. Park, S., Pascua, E., Lindquist, K. C., Kimberlin, C., Deng, X., Mak, Y. S. L., Melton, Z., Johnson, T. O., Lin, R., Boldajipour, B., Abraham, R. T., Pons, J., Sasu, B. J., Van Blarcom, T. J., & Chaparro-Riggers, J. (2021). Direct control of CAR T cells through small molecule-regulated antibodies. Nature Communications, 12, 710. https://doi.org/10.1038/s41467-020-20671-6
[38]. Kenderian, S., Ruella, M., Shestova, O., Klichinsky, M., Aikawa, V., Morrissette, J., Scholler, J., Song, D., Porter, D., Carroll, M., June, C., & Gill, S. (2015). CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia, 29(8), 1637–1647. https://doi.org/10.1038/leu.2015.52
[39]. Zhang, Y., Wallace, D. L., de Lara, C. M., Ghattas, H., Asquith, B., Worth, A., Griffin, G. E., Taylor, G. P., Tough, D. F., Beverley, P. C. L., & Macallan, D. C. (2007). In vivo kinetics of human natural killer cells: The effects of ageing and acute and chronic viral infection. Immunology, 121(2), 258–265. https://doi.org/10.1111/j.1365-2567.2007.02573.x
[40]. Xie, G., Dong, H., Liang, Y., Ham, J. D., Rizwan, R., & Chen, J. (2020). CAR-NK cells: A promising cellular immunotherapy for cancer. EBioMedicine, 59, 102975. https://doi.org/10.1016/j.ebiom.2020.102975
Cite this article
Huang,H. (2025). Challenges and innovations in managing cytokine release syndrome in CAR-T therapy: mechanisms, clinical impact, and future directions. Theoretical and Natural Science,77,133-140.
Data availability
The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.
Disclaimer/Publisher's Note
The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of EWA Publishing and/or the editor(s). EWA Publishing and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
About volume
Volume title: Proceedings of ICBioMed 2024 Workshop: Computational Proteomics in Drug Discovery and Development from Medicinal Plants
© 2024 by the author(s). Licensee EWA Publishing, Oxford, UK. This article is an open access article distributed under the terms and
conditions of the Creative Commons Attribution (CC BY) license. Authors who
publish this series agree to the following terms:
1. Authors retain copyright and grant the series right of first publication with the work simultaneously licensed under a Creative Commons
Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this
series.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the series's published
version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial
publication in this series.
3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and
during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See
Open access policy for details).