Application of multi-targeted CAR-T cell therapy in B-cell acute lymphoblastic leukemia

doi:10.16352/j.issn.1001-6325.2025.05.0675

Abstract

Abstract: Chimeric antigen receptor-modified T (CAR-T) cell therapy, as a new type of cellular immunotherapy, has shown good clinical efficacy in the treatment of malignant hematological tumors, especially B-cell acute lymphoblastic leukemia. However, there are problems such as antigen loss and immune evasion in single-target selection, so multi-target therapy strategies are gradually gaining attention. Multi-target CAR-T can effectively avoid antigen escape caused by a single target by targeting multiple tumor-associated antigens at the same time, reduce the risk of recurrence, and is expected to improve the therapeutic effect. This paper primarily discusses the structural types of multi-target CAR-T cell therapy and its clinical trial applications in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), aiming to provide future references for the treatment of B-ALL.

Key words: multi-target, CAR-T cell therapy, B-cell acute lymphoblastic leukemia, off-target effect, tumor-associated antigen

CLC Number:

R739.6

CAO Jinjin, DU Juan, QU Shanna, ZHU Mingyu, WANG Yang, HU Han, LIU Binlei. Application of multi-targeted CAR-T cell therapy in B-cell acute lymphoblastic leukemia[J]. Basic & Clinical Medicine, 2025, 45(5): 675-680.

References

[1]Cao W,Qin K, Li F, et al.Comparative study of cancer profiles between 2020 and 2022 using global cancer statistics (GLOBOCAN)[J].Natl Cancer Cent,2024,4:128-134.
[2]Green S, Schultz L. Rational alternatives to fludarabine and cyclophosphamide-based pre-CAR lymphodepleting regimens in the pediatric and young adult B-ALLsetting[J].Curr Oncol Rep,2023,25:841-846.
[3]Maude SL,Laetsch TW,Buechner J,et al.Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia[J].N Engl J Med,2018,378:439-448.
[4]冯友琴,张棋琦,胡永仙,等.多靶点CAR-T治疗血液系统恶性肿瘤研究进展[J].临床内科杂志,2022,39:577-582.
[5]Bagley SJ,Logun M,Fraietta JA,et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results[J].Nat Med,2024,30:1320-1329.
[6]Wang W,He S,Zhang W,et al. BCMA-CD19 compound CAR T cells for systemic lupus erythematosus a phase 1 open-label clinical trial[J].Ann Rheum Dis,2024,83:1304-1314.
[7]Roddie C,Lekakis LJ,Marzolini MAV,et al. Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B-cell lymphoma[J].Blood,2023,141:2470-2482.
[8]Shalabi H,Qin H,Su A,et al. CD19/22 CAR T cells in children and young adults with B-ALL phase 1 results and development of a novel bicistronic CAR[J].Blood, 2022,140:451-463.
[9]Liu Y,Deng B,Hu B,et al. Sequential different B-cell antigen-targeted CAR T-cell therapy for pediatric refractory/relapsed Burkitt lymphoma[J].Blood Adv,2022,6:717-730.
[10]Bachiller M,Barceló-Genestar N,Rodriguez-Garcia A,et al. ARI0003: co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma[J].Mol Ther,2025,33:317-335.
[11]Othman T,Logan AC,Muffly L,et al. The role of CAR T-cell therapy in relapsed/refractory adult B-ALL[J].Natl Compr CancNetw,2024,22:e247065. doi:10.6004/jnccn.2024.7065.
[12]Cordoba S,Onuoha S,Thomas S,et al. CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia a phase 1 trial[J].Nat Med,2021,27:1797-1805.
[13]Fergusson NJ,Adeel K,Kekre N,et al.A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells[J].Front Immunol,2023,14:1178403.doi:10.3389/fimmu.2023.1178403
[14]Sining L,Qingya C,Zheng L,et al. Efficacy and safety of the second CAR-T therapy in patients with refractory/relapsed aute B-cell lymphoblastic leukemia[J].Blood,2023,142:3491. doi:10.1182/blood-2023-186718.
[15]Zah E,Lin MY,Silva-Benedict A,et al. T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells[J].Cancer Immunol Res,2016,4:498-508.
[16]Martyniszyn A,Krahl AC,André MC,et al. CD20-CD19 bispecific CAR-T cells for the treatment of B-Cell malignancies[J].Hum Gene Ther,2017,28:1147-1157.
[17]Yang N,Zhang C,Zhang Y,et al. CD19/CD20 dual-targeted chimeric antigen receptor-engineered natural killer cells exhibit improved cytotoxicity against acute lymphoblastic leukemia[J].J Transl Med,2024,22:274. doi:10.1186/s12967-024-04990-6.
[18]Khaniya A,Rad SMAH,Halpin J,et al. Development of a compact bidirectional promoter-driven dual chimeric antigen receptor (CAR) construct targeting CD19 and CD20 in the Sleeping Beauty (SB) transposon system[J].Immunother Cancer,2024,12:e008555.doi:10.1136/jitc-2023-008555.
[19]Ren HW,Elliott N,Lye B,et al. Bispecific CAR-iNKT immunotherapy for high risk mll-rearranged acute lymphoblastic leukemia[J].Blood,2023,142: 766.doi:10.1182/blood-2023-186442.
[20]Schneider D,Xiong Y,Wu D, et al. Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models[J].Sci Transl Med,2021,13:6401.doi:10.1126/scitranslmed.abc6401.
[21]Shokouhi AR,Chen Y,Yoh HZ,et al. Engineering efficient CAR-T cells via electroactive nanoinjection[J].Adv Mater,2023,35: e2304122. doi:10.1002/adma. 202304122.
[22]Ku KS,Tang J,Chen Y,et al.Current advancements in anti-cancer chimeric antigen receptor T cell immuno-therapy and how nanotechnology may change the game[J].Int J Mol Sci,2024,25:5361. doi:10.3390/ijms25105361.
[23]Fu Y,Wang T,Ronald JA. A synthetic notch (synNotch) system linking intratumoral immune-cancer cell communication to a synthetic blood biomarker assay[J].Front Pharmacol,2023,14:1304194.doi:10.3389/fphar.2023.1304194.
[24]Bouquet L,Bôle-Richard E,Warda W,et al. Rapa Caspase-9-based suicide gene applied to the safety of IL-1RAP CAR-T cells[J].Gene Ther,2023,30:706-713.
[25]Chohan KL,Siegler EL,Kenderian SS. CAR-T cell therapy the efficacy and toxicity balance[J].Curr Hematol Malig Rep,2023,18:9-18.