儿童CAR-T细胞治疗的挑战与展望

doi:10.12372/jcp.2024.24e0578

摘要/Abstract

摘要：

嵌合抗原受体T细胞（CAR-T）首次应用于治疗急性淋巴细胞白血病复发患儿已有10年余，至今全世界范围内已有成千上万的患者从中受益，CAR-T细胞治疗在很大程度上提高了复发、难治儿童急性淋巴细胞白血病患者的整体预后，同时也正在逐渐改变着复发、难治儿童血液肿瘤患者的治疗历史。目前的研究显示，儿童CAR-T细胞治疗前景光明，但临床上仍面临着一些挑战。

关键词: 嵌合抗原受体T细胞, 挑战, 展望, 儿童

Abstract:

It has been more than 10 years since chimeric antigen receptor T cells (CAR-T) therapy were first used to treat children with relapsed acute lymphoblastic leukemia, and thousands of patients worldwide have benefited from it. CAR-T treatment has greatly improved the overall prognosis of relapsed and refractory pediatric acute lymphoblastic leukemia patients and is gradually changing the treatment history of relapsed and refractory pediatric hematological tumor patients. Currently, CAR-T treatment for children still faces some challenges, but overall, the prospects are extremely promising.

Key words: chimeric antigen receptor T cell, challenge, prospect, child

李本尚, 杨柳. 儿童CAR-T细胞治疗的挑战与展望[J]. 临床儿科杂志, 2024, 42(7): 573-577.

LI Benshang, YANG Liu. Challenges and prospects of CAR-T treatment for pediatric disease[J]. Journal of Clinical Pediatrics, 2024, 42(7): 573-577.

参考文献 40

[1]	Daei Sorkhabi A, Mohamed Khosroshahi L, Sarkesh A, et al. The current landscape of CAR T-cell therapy for solid tumors: mechanisms, research progress, challenges, and counterstrategies[J]. Front Immunol, 2023, 14: 1113882.
[2]	Pui CH, Yang JJ, Hunger SP, et al. Childhood acute lymphoblastic leukemia: progress through collaboration[J]. J Clin Oncol, 2015, 33(27): 2938-2948.
[3]	Gupta A, Cripe TP. Immunotherapies for pediatric solid tumors: a targeted update[J]. Paediatr Drugs, 2022, 24(1): 1-12.
[4]	Wang F, Fu K, Wang Y, et al. Small-molecule agents for cancer immunotherapy[J]. Acta Pharm Sin B, 2024, 14(3): 905-952. doi: 10.1016/j.apsb.2023.12.010 pmid: 38486980
[5]	Cuesta-Mateos C, Alcaraz-Serna A, Somovilla-Crespo B, et al. Monoclonal antibody therapies for hematological malignancies: not just lineage-specific targets[J]. Front Immunol, 2017, 8: 1936. doi: 10.3389/fimmu.2017.01936 pmid: 29387053
[6]	Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far[J]. Nat Rev Clin Oncol, 2023, 20(6): 359-371. doi: 10.1038/s41571-023-00754-1 pmid: 37055515
[7]	Talleur AC, Qudeimat A, Métais JY, et al. Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL[J]. Blood Adv, 2022, 6(21): 5737-5749.
[8]	Zhu M, Wu B, Brandl C, et al. Blinatumomab, a bispecific T-cell engager (BiTE®) for CD19^- targeted cancer immunotherapy: clinical pharmacology and its implications[J]. Clin Pharmacokinet, 2016, 55(10): 1271-1288.
[9]	Wang T, Tang Y, Cai J, et al. Coadministration of CD19- and CD22-directed chimeric antigen receptor T-Cell therapy in childhood B-cell acute lymphoblastic leukemia: a single-arm, multicenter, phase Ⅱ trial[J]. J Clin Oncol, 2023, 41(9): 1670-1683.
[10]	Xiao X, Huang S, Chen S, et al. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies[J]. J Exp Clin Cancer Res, 2021, 40(1): 367. doi: 10.1186/s13046-021-02148-6 pmid: 34794490
[11]	Siegler EL, Kenderian SS. Neurotoxicity and cytokine release syndrome after chimeric antigen receptor T cell therapy: insights into mechanisms and novel therapies[J]. Front Immunol, 2020, 11: 1973. doi: 10.3389/fimmu.2020.01973 pmid: 32983132
[12]	Hines MR, Knight TE, McNerney KO, et al. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome[J]. Transplant Cell Ther, 2023, 29(7): 438.
[13]	Wat J, Barmettler S. Hypogammaglobulinemia after chimeric antigen receptor CAR T-cell therapy: characteristics, management, and future directions[J]. J Allergy Clin Immunol Pract, 2022, 10(2): 460-466.
[14]	Jain MD, Smith M, Shah NN. How I treat refractory CRS and ICANS after CAR T-cell therapy[J]. Blood, 2023, 141(20): 2430-2442.
[15]	Zhang Y, Zhou F, Wu Z, et al. Timing of tocilizumab administration under the guidance of IL-6 in CAR-T therapy for R/R acute lymphoblastic leukemia[J]. Front Immunol, 2022, 13:914959.
[16]	Rainone M, Ngo D, Baird JH, et al. Interferon-γ blockade in CAR T-cell therapy-associated macrophage activation syndrome/hemophagocytic lymphohistiocytosis[J]. Blood Adv, 2023, 7(4): 533-536.
[17]	Manni S, Del Bufalo F, Merli P, et al. Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies[J]. Nat Commun, 2023, 14(1): 3423. doi: 10.1038/s41467-023-38723-y pmid: 37296093
[18]	Xu N, Yang XF, Xue SL, et al. Ruxolitinib reduces severe CRS response by suspending CAR-T cell function instead of damaging CAR-T cells[J]. Biochem Biophys Res Commun, 2022, 595: 54-61.
[19]	Mestermann K, Giavridis T, Weber J, et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells[J]. Sci Transl Med, 2019, 11(499): eaau5907.
[20]	Ventin M, Cattaneo G, Maggs L, et al. Implications of high tumor burden on chimeric antigen receptor T-Cell immunotherapy: a review[J]. JAMA Oncol, 2024, 10(1): 115-121.
[21]	Sterner RC, Sterner RM. Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy[J]. Front Immunol, 2022, 13:879608.
[22]	Gu T, Hu K, Si X, et al. Mechanisms of immune effector cell-associated neurotoxicity syndrome after CAR-T treatment[J]. WIREs Mech Dis, 2022, 14(6): e1576.
[23]	Sheth VS, Gauthier J. Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL[J]. Bone Marrow Transplant, 2021, 56(3): 552-566.
[24]	Gatto L, Ricciotti I, Tosoni A, et al. CAR-T cells neurotoxicity from consolidated practice in hematological malignancies to fledgling experience in CNS tumors: fill the gap[J]. Front Oncol, 2023, 13: 1206983.
[25]	Nix MA, Mandal K, Geng H, et al. Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in KMT2A/MLL1-rearranged B-ALL[J]. Cancer Discov, 2021, 11(8): 2032-2049. doi: 10.1158/2159-8290.CD-20-0242 pmid: 33727310
[26]	Leung KT, Cai J, Liu Y, et al. Prognostic implications of CD9 in childhood acute lymphoblastic leukemia: insights from a nationwide multicenter study in China[J]. Leukemia, 2024, 38(2): 250-257. doi: 10.1038/s41375-023-02089-3 pmid: 38001171
[27]	Zhao Z, Sadelain M. CAR T cell design: approaching the elusive AND-gate[J]. Cell Res, 2023, 33(10): 739-740. doi: 10.1038/s41422-023-00828-w pmid: 37221269
[28]	Coorens THH, Collord G, Treger TD, et al. Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy[J]. Nature Cancer, 2023, 4(8): 1095-1101.
[29]	Gu R, Liu W, Mei Y, et al. The impact of ZNF384 rearranged on antigen editing during treatment-specific selective pressures in adult B cell acute lymphoid leukemia[J]. Blood, 2023, 142: 4209.
[30]	De Bie J, Demeyer S, Gielen O, et al. BCR-ABL1 positive B-ALL can undergo T-cell lineage shift to become CD19 negative T-ALL[J]. HemaSphere, 2018, 2(3): e42.
[31]	Liang M, Gong D, Wang L, et al. PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by high expression of immune inhibitory-related molecules[J]. Cancer Treat Res Commun, 2021, 28: 100437.
[32]	Majzner RG, Ramakrishna S, Yeom KW, et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas[J]. Nature, 2022, 603(7903): 934-941.
[33]	Bufalo FD, Angelis BD, Caruana I, et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma[J]. N Engl J Med, 2023, 388(14): 1284-1295.
[34]	Maalej KM, Merhi M, Inchakalody VP, et al. CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances[J]. Mol Cancer, 2023, 22(1): 20. doi: 10.1186/s12943-023-01723-z pmid: 36717905
[35]	Ayala Ceja M, Khericha M, Harris CM, et al. CAR-T cell manufacturing: major process parameters and next-generation strategies[J]. J Exp Med, 2024, 221(2): e20230903.
[36]	Yang J, He J, Zhang X, et al. Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study[J]. Blood Cancer J, 2022, 12(7): 104. doi: 10.1038/s41408-022-00694-6 pmid: 35798714
[37]	Lin H, Cheng J, Mu W, et al. Advances in universal CAR-T cell therapy[J]. Front Immunol, 2021, 12:744823.
[38]	Jo S, Das S, Williams A, et al. Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing[J]. Nat Commun, 2022, 13(1): 3453. doi: 10.1038/s41467-022-30896-2 pmid: 35773273
[39]	Muller F, Taubmann J, Bucci L, et al. CD19 CAR T-cell therapy in autoimmune disease - a case series with follow-up[J]. N Engl J Med, 2024, 390(8): 687-700.
[40]	Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases[J]. Lancet, 2023, 402(10416): 2034-2044. doi: 10.1016/S0140-6736(23)01126-1 pmid: 37748491