多发性骨髓瘤患者的CAR T细胞疗法的临床进展
Clinical Advances in CAR T Cell Therapies for the Patients with Multiple Myeloma
DOI: 10.12677/ACM.2023.1361478, PDF,   
作者: 韦学玉：青海大学研究生院，青海 西宁；耿 惠*：青海大学附属医院血液科，青海 西宁
关键词: 多发性骨髓瘤；嵌合抗原受体T细胞；Multiple Myeloma； Chimeric Antigen Receptors-T Cells
摘要: 多发性骨髓瘤(Multiple myeloma, MM)是一种目前依然无法治愈的浆细胞恶性肿瘤。B细胞和MM细胞的小子集上表达，这使其成为用于此类疗法的合适靶抗原。在撰写本文时，来自>20项涉及抗BCMA CAR T细胞的临床试验的数据已经证明，复发性和/或难治性MM患者可以实现客观反应。这些早期研究有助于证明短期安全性和有效性；然而，大多数患者没有持续>18个月的疾病缓解。减少或延迟复发性疾病发作的尝试正在进行中，并且包括鉴定另外的CAR T细胞靶抗原和增强MM细胞上BCMA表达的方法。CAR T细胞以增强治疗的活性和安全性仍然是一种有希望的改进途径。在这篇综述中，我们总结了迄今为止进行的临床试验的数据，描述了未来可能靶向的新型抗原，并强调了未来可能提高CAR T细胞疗法疗效和/或降低其毒性的潜在创新。
Abstract: Multiple myeloma (MM) is a malignancy of plasma cells that remains incurable. Expressed on a small subset of B cells and MM cells, which makes it a suitable target antigen for this type of therapy. At the time of writing, data from >20 clinical trials involving anti-BCMA CAR T cells have demon-strated that objective responses can be achieved in patients with relapsed and/or refractory MM. These early studies help demonstrate short-term safety and efficacy; However, most patients did not have remission that lasted >18 months. Attempts to reduce or delay the onset of recurrent dis-ease are ongoing and include methods to identify additional CAR T cell target antigens and enhance BCMA expression on MM cells. CAR T cells to enhance the activity and safety of treatments remains a promising avenue for improvement. In this review, we summarize data from clinical trials con-ducted to date, describe novel antigens that may be targeted in the future, and highlight potential innovations that may improve the efficacy and/or reduce the toxicity of CAR T cell therapies in the future.
文章引用：韦学玉, 耿惠. 多发性骨髓瘤患者的CAR T细胞疗法的临床进展[J]. 临床医学进展, 2023, 13(6): 10568-10573. https://doi.org/10.12677/ACM.2023.1361478

参考文献

[1] Röllig, C., Knop, S. and Bornhäuser, M. (2015) Multiple Myeloma. The Lancet (London, England), 385, 2197-2208. [Google Scholar] [CrossRef] 
[2] Sadelain, M., Brentjens, R. and Rivière, I. (2013) The Basic Principles of Chimeric Antigen Receptor Design. Cancer Discovery, 3, 388-398. [Google Scholar] [CrossRef] 
[3] Kochenderfer, J.N. and Rosenberg, S.A. (2013) Treating B-Cell Cancer with T Cells Expressing Anti-CD19 Chimeric Antigen Receptors. Nature Reviews. Clinical Oncology, 10, 267-276. [Google Scholar] [CrossRef] [PubMed]
[4] Maus, M.V., Grupp, S.A., Porter, D.L. and June, C.H. (2014) Antibody-Modified T Cells: CARs Take the Front Seat for Hematologic Malignancies. Blood, 123, 2625-2635. [Google Scholar] [CrossRef] [PubMed]
[5] Kershaw, M.H., Westwood, J.A. and Darcy, P.K. (2013) Gene-Engineered T Cells for Cancer Therapy. Nature Reviews Cancer, 13, 525-541. [Google Scholar] [CrossRef] [PubMed]
[6] Holzinger, A. and Abken, H. (2019) CAR T Cells: A Snapshot on the Grow-ing Options to Design a CAR. HemaSphere, 3, e172. [Google Scholar] [CrossRef] 
[7] Ramos, C.A., Savoldo, B., Torrano, V., Ballard, B., Zhang, H., Dakhova, O., Liu, E., Carrum, G., Kamble, R.T., Gee, A.P., Mei, Z., Wu, M.F., Liu, H., Grilley, B., Rooney, C.M., Brenner, M.K., Heslop, H.E. and Dotti, G. (2016) Clinical Responses with T Lymphocytes Targeting Malignancy-Associated κ Light Chains. The Journal of Clinical Investigation, 126, 2588-2596. [Google Scholar] [CrossRef] 
[8] Levine, B.L., Miskin, J., Wonnacott, K. and Keir, C. (2016) Global Manufacturing of CAR T Cell Therapy. Molecular Therapy. Methods & Clinical Development, 4, 92-101. [Google Scholar] [CrossRef] [PubMed]
[9] Kumar, S.K., Rajkumar, V., Kyle, R.A., van Duin, M., Sonneveld, P., Mateos, M.V., Gay, F. and Anderson, K.C. (2017) Multiple Myeloma. Nature Reviews Disease Primers, 3, Article No. 17046. [Google Scholar] [CrossRef] [PubMed]
[10] Sadelain, M., Rivière, I. and Riddell, S. (2017) Therapeutic T Cell Engi-neering. Nature, 545, 423-431. [Google Scholar] [CrossRef] [PubMed]
[11] Kochenderfer, J.N., Somerville, R.P.T., Lu, T., Shi, V., Bot, A., Rossi, J., Xue, A., Goff, S.L., Yang, J.C., Sherry, R.M., Klebanoff, C.A., Kammula, U.S., Sherman, M., Perez, A., Yuan, C.M., Feldman, T., Friedberg, J.W., Roschewski, M.J., Feldman, S.A., McIntyre, L. and Rosenberg, S.A. (2017) Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated with High Serum Interleukin-15 Levels. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 35, 1803-1813. [Google Scholar] [CrossRef] 
[12] Brudno, J.N. and Kochenderfer, J.N. (2018) Chimeric Antigen Receptor T-Cell Therapies for Lymphoma. Nature Reviews Clinical Oncology, 15, 31-46. [Google Scholar] [CrossRef] [PubMed]
[13] Neelapu, S.S., Locke, F.L., Bartlett, N.L., Lekakis, L.J., Miklos, D.B., Jacobson, C.A., Braunschweig, I., Oluwole, O.O., Siddiqi, T., Lin, Y., Timmerman, J.M., Stiff, P.J., Friedberg, J.W., Flinn, I.W., Goy, A., Hill, B.T., Smith, M.R., Deol, A., Farooq, U., McSweeney, P. and Go, W.Y. (2017) Axi-cabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. The New England Journal of Medicine, 377, 2531-2544. [Google Scholar] [CrossRef] 
[14] Schuster, S.J., Svoboda, J., Chong, E.A., Nasta, S.D., Mato, A.R., Anak, Ö., Brogdon, J.L., Pruteanu-Malinici, I., Bhoj, V., Landsburg, D., Wasik, M., Levine, B.L., Lacey, S.F., Melen-horst, J.J., Porter, D.L. and June, C.H. (2017) Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. The New England Journal of Medicine, 377, 2545-2554. [Google Scholar] [CrossRef] 
[15] Lim, W.A. and June, C.H. (2017) The Principles of Engineering Immune Cells to Treat Cancer. Cell, 168, 724-740. [Google Scholar] [CrossRef] [PubMed]
[16] Zhao, W.H., Liu, J., Wang, B.Y., Chen, Y.X., Cao, X.M., Yang, Y., Zhang, Y.L., Wang, F.X., Zhang, P.Y., Lei, B., Gu, L.F., Wang, J.L., Yang, N., Zhang, R., Zhang, H., Shen, Y., Bai, J., Xu, Y., Wang, X.G., Zhang, R.L. and Zhang, W.G. (2018) A Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed against B Cell Maturation Antigen, in Patients with Relapsed or Refractory Multiple Myeloma. Journal of Hematology & Oncology, 11, Article No. 141. [Google Scholar] [CrossRef] [PubMed]
[17] Yan, Z., Zhang, H., Cao, J., et al. (2021) Characteristics and Risk Factors of Cytokine Release Syndrome in Chimeric Antigen Receptor T Cell Treatment. Frontiers in Immunology, 12, Article ID: 611366. [Google Scholar] [CrossRef] [PubMed]
[18] Wang, X. and Rivière, I. (2016) Clinical Manufacturing of CAR T Cells: Foundation of a Promising Therapy. Molecular Therapy Oncolytics, 3, Article No. 16015. [Google Scholar] [CrossRef] [PubMed]
[19] Brudno, J.N. and Kochenderfer, J.N. (2019) Recent Advances in CAR T-Cell Toxicity: Mechanisms, Manifestations and Management. Blood Reviews, 34, 45-55. [Google Scholar] [CrossRef] [PubMed]
[20] 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., van den Brink, M.R.M., Komanduri, K.V. and 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: Journal of the American Society for Blood and Marrow Trans-plantation, 25, 625-638. [Google Scholar] [CrossRef] [PubMed]
[21] Cohen, A.D., Garfall, A.L., Stadtmauer, E.A., Melenhorst, J.J., Lacey, S.F., Lancaster, E., Vogl, D.T., Weiss, B.M., Dengel, K., Nelson, A., Plesa, G., Chen, F., Davis, M.M., Hwang, W.T., Young, R.M., Brogdon, J.L., Isaacs, R., Pruteanu-Malinici, I., Siegel, D.L., Levine, B.L. and Milone, M.C. (2019) B Cell Maturation Antigen-Specific CAR T Cells Are Clinically Active in Multiple Myeloma. The Journal of Clinical Investigation, 129, 2210-2221. [Google Scholar] [CrossRef] 
[22] Srivastava, S. and Riddell, S.R. (2015) Engineering CAR-T Cells: Design Concepts. Trends in Immunology, 36, 494-502. [Google Scholar] [CrossRef] [PubMed]
[23] Baumeister, S.H., Murad, J., Werner, L., Daley, H., Trebeden-Negre, H., Gicobi, J.K., Schmucker, A., Reder, J., Sentman, C.L., Gilham, D.E., Lehmann, F.F., Galinsky, I., DiPietro, H., Cummings, K., Munshi, N.C., Stone, R.M., Neuberg, D.S., Soiffer, R., Dranoff, G., Ritz, J. and Nikiforow, S. (2019) Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. Cancer Immunology Research, 7, 100-112. [Google Scholar] [CrossRef] 
[24] Schaefer, A., et al. (2019) Cytopenias after Chimeric Antigen Receptor T-Cells (CAR-T) Infusion; Patterns and Outcomes. Biology of Blood and Marrow Transplantation, 25, S171. [Google Scholar] [CrossRef] 
[25] Mei, H., Li, C., Jiang, H., Zhao, X., Huang, Z., Jin, D., Guo, T., Kou, H., Liu, L., Tang, L., Yin, P., Wang, Z., Ai, L., Ke, S., Xia, Y., Deng, J., Chen, L., Cai, L., Sun, C., Xia, L. and Hu, Y. (2021) A Bispecific CAR-T Cell Therapy Targeting BCMA and CD38 in Relapsed or Refractory Multiple Myeloma. Journal of Hematology & Oncology, 14, Article No. 161. [Google Scholar] [CrossRef] [PubMed]
[26] Porter, D., Frey, N., Wood, P.A., Weng, Y. and Grupp, S.A. (2018) Grading of Cytokine Release Syndrome Associated with the CAR T Cell Therapy Tisagenlecleucel. Journal of Hematology & Oncology, 11, Article No. 35. [Google Scholar] [CrossRef] [PubMed]
[27] Lee, D.W., Gardner, R., Porter, D.L., Louis, C.U., Ahmed, N., Jensen, M., Grupp, S.A. and Mackall, C.L. (2014) Current Concepts in the Diagnosis and Management of Cytokine Re-lease Syndrome. Blood, 124, 188-195. [Google Scholar] [CrossRef] [PubMed]
[28] Xu, J., Chen, L.J., Yang, S.S., Sun, Y., Wu, W., Liu, Y.F., Xu, J., Zhuang, Y., Zhang, W., Weng, X.Q., Wu, J., Wang, Y., Wang, J., Yan, H., Xu, W.B., Jiang, H., Du, J., Ding, X.Y., Li, B., Li, J.M. and Chen, S.J. (2019) Exploratory Trial of a Biepitopic CAR T-Targeting B Cell Maturation Antigen in Relapsed/Refractory Multiple Myeloma. Proceedings of the National Academy of Sciences of the United States of Ameri-ca, 116, 9543-9551. [Google Scholar] [CrossRef] [PubMed]
[29] Carpenter, R.O., Evbuomwan, M.O., Pittaluga, S., Rose, J.J., Raf-feld, M., Yang, S., Gress, R.E., Hakim, F.T. and Kochenderfer, J.N. (2013) B-Cell Maturation Antigen Is a Promising Target for Adoptive T-Cell Therapy of Multiple Myeloma. Clinical Cancer Research: An Official Journal of the Ameri-can Association for Cancer Research, 19, 2048-2060. [Google Scholar] [CrossRef] 
[30] Smith, E.L., Harrington, K., Staehr, M., Masakayan, R., Jones, J., Long, T.J., Ng, K.Y., Ghoddusi, M., Purdon, T.J., Wang, X., Do, T., Pham, M.T., Brown, J.M., De Larrea, C.F., Olson, E., Peguero, E., Wang, P., Liu, H., Xu, Y., Garrett-Thomson, S.C. and Brentjens, R.J. (2019) GPRC5D Is a Target for the Immunotherapy of Multiple Myeloma with Rationally De-signed CAR T Cells. Science Translational Medicine, 11, eaau7746. [Google Scholar] [CrossRef] [PubMed]
[31] Boudreault, J.S., Touzeau, C. and Moreau, P. (2017) The Role of SLAMF7 in Multiple Myeloma: Impact on Therapy. Expert Review of Clinical Immunology, 13, 67-75. [Google Scholar] [CrossRef] 

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