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Novel CAR T-cell therapies for relapsed/refractory B-cell malignancies: latest updates from 2023 ASH annual meeting


Chimeric antigen receptors (CAR) are engineered fusion proteins that target T-cells to specific surface antigens of tumor cells to generate effective anti-tumor responses. CAR T-cell therapy is playing an increasingly important role in the treatment of relapsed/refractory B-cell malignancies (R/R BCM). Attempting to make CAR T-cells safer and more effective in treating R/R BCM, various novel engineered CAR T-cell agents are currently in the research and development or clinical trial stages. We have summarized here the latest reports on the novel CAR T-cell therapies for R/R BCM presented at the 2023 ASH Annual Meeting as well as the latest updates in related clinical trials.

To the editor

CAR T-cell therapy has become an effective treatment for relapsed/refractory B-cell malignancies (R/R BCM). However, due to serious adverse events and failure to control or eradicate malignancies, many patients still cannot benefit from CAR T-cell therapy [1]. How to make CAR T-cells produce durable, effective, and safe anti-tumor effects remains a key issue. For this purpose, new targets are being studied or screened, and CAR T-cells are also being redesigned and modified [2]. Variously engineered CAR T-cells are in clinical trials. We have summarized the latest reports on novel CAR T-cell therapies for R/R BCM from the 2023 ASH Annual Meeting (ASH 2023) as well as the latest updates related to clinical trials.

Novel modified CD19 targeted CAR T-cell therapy

CD19 CAR T-cells have always been the mainstay of CAR T-cell therapy for R/R BCM [3]. However, successful CAR T-cell therapy not only requires effective and durable clinical efficacy but also safe and tolerable toxicity [4]. At ASH 2023, several studies reported novel modified CD19 targeted CAR T-cell agents that not only ensure CAR T-cells efficacy but also alleviate adverse events such as severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Kang et al. reported novel CD19 targeted CAR T-cells incorporating a small hairpin RNA element to silence the interleukin-6 gene (ssCART-19), reducing the incidence of severe CRS and neurotoxicity in R/R B-cell acute lymphoblastic leukemia patients [5]. Compared with the control group the incidence of grade 3–4 CRS in the ssCART-19 group decreased by 22.61% and there was no occurrence of grade 3–4 ICANS. The complete response (CR) or CR with incomplete hematological recovery (CRi) rate of ssCART-19 treatment on day 28 was 91.49%. Another Phase 1 trial on a novel third generation CD19 directed CAR T-cells incorporating CD28 and Toll-like receptor 2 co-stimulatory domains mitigated the risk of CAR T-cell therapy related ICANS while maintaining therapeutic efficacy in R/R B-cell non-Hodgkin’s lymphoma (NHL) [6]. There was no grade ≥ 3 CRS or any grade ICANS during the treatment period, and there was still a 52% CR at month three. Park et al. created a novel CD19 CAR construct with calibrated CAR activation potential by mutating 2 out of 3 immunoreceptor tyrosine-based activation motifs, called 19(T2)28z1XX [7]. Patients with R/R diffuse large B-cell lymphomas (DLBCL) receiving 19(T2)28z1XX CAR T-cell therapy showed persistent remission, with an overall CR rate of 71%, and a low incidence of severe CRS (4%) and ICANS (7%). Zheng et al. reported the latest clinical data of non-viral programmed cell death protein-1 locus specifically integrated anti-CD19 CAR T-cells (BRL-201) generated using CRISPR-Cas9 for the treatment of R/R NHL, with a median follow-up period of 29 months [8]. BRL-201 provided a safe and effective clinical response with an objective response rate (ORR) of 100% and a CR rate of 85.7%, while no grade 3–4 CRS or ICANS were observed.

Novel CAR T-cell therapy targeting ROR-1, CD70 and dual antigens

Several studies reported the latest clinical trial data on CAR T-cells engineered to recognize new targets for the treatment of R/R BCM. Abramson et al. reported the preliminary results of UCART20×22, a dual allogeneic CAR T-cell product targeting CD20 and CD22 in R/R NHL [9]. All three enrolled patients responded with two CRs and one PR on day 28. Meanwhile, UCART20×22 exhibited good safety and acceptable toxicity. Tu et al. published the results of CD19/CD70 CAR T-cell therapy for R/R DLBCL [10]. The CR rate at 1 month reached 75.0%. After a median follow-up time of 19.9 months, 50% of patients still maintained CR, with a median disease-free survival of 10.5 months. No patients experienced a grade ≥ 3 CRS or any grade ICANS. In addition, a bispecific anti-CD20/CD19 CAR T-cell agent, C-CAR039, demonstrated durable responses and good safety in R/R B-NHL therapy [11]. The ORR and CR rates were 91.5% and 85.1%. Meanwhile, only one patient (2.1%) experienced severe CRS and there was no occurrence of severe ICANS. Another ongoing phase 1/2 trial is evaluating the effectiveness and safety of ROR1-specific CAR T-cell therapy for R/R aggressive B-cell lymphoma, including LBCL and Mantle cell lymphoma [12]. This study consists of two stages: phase 1 is for dose escalation while phase 2 is for dose expansion.

In conclusion, ASH 2023 presented the prospects and progress of novel CAR T-cell therapies for the treatment of R/R BCM as summarized in Tables 1 and 2. At present, the failure of CAR T-cell therapy is usually attributed to the loss of target antigens or depletion of CAR T-cells, while dual antigen targeting and CAR T-cells modification are potential strategies to overcome treatment failure. Therefore, the emergence of novel CAR T-cell therapies will further improve the treatment safety and effectiveness of patients with R/R BCM.

Table 1 Novel CAR T-cell agents for relapsed/refractory B-cell malignancies
Table 2 The efficacy and safety of novel CAR T-cells

Data availability

The material supporting the conclusion of this study has been included within the article.



American Society of Hematology


Chimeric antigen receptor




B-cell malignancies


Diffuse large B-cell lymphomas


Non-Hodgkin’s lymphoma


Cytokine release syndrome


Immune effector cell-associated neurotoxicity syndrome


Complete response


CR with incomplete hematological recovery


Objective response rate


Progression free survival


Overall survival


  1. Frigault MJ, Maus MV. State of the art in CAR T cell therapy for CD19 + B cell malignancies. J Clin Invest. 2020;130(4):1586–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang Z, Wu Z, Liu Y, Han W. New development in CAR-T cell therapy. J Hematol Oncol. 2017;10(1):53.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Huang R, Li X, He Y, Zhu W, Gao L, Liu Y, et al. Recent advances in CAR-T cell engineering. J Hematol Oncol. 2020;13(1):86.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Louie RHY, Cai C, Samir J, Singh M, Deveson IW, Ferguson JM, et al. CAR(+) and CAR(-) T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies. Nat Commun. 2023;14(1):7767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kang L, Ma J, Lou X, Tang X, Xue S, Chen S, et al. Efficacy and safety of Interleukin-6-Knockdown CD19-Targeted CAR T cells(ssCART-19) for Relapsed/Refractory B-ALL. Blood. 2023;142(Supplement 1):889.

    Article  Google Scholar 

  6. Weinkove R, George P, Fyfe R, Dasyam N, Nouri Y, Ostapowicz T, et al. A phase 1 dose escalation Trial of Third-Generation CD19-Directed CAR T-Cells incorporating CD28 and toll-like receptor 2 (TLR2) intracellular domains for relapsed or refractory B-Cell Non-hodgkin Lymphomas (ENABLE). Blood. 2023;142(Supplement 1):890.

    Article  Google Scholar 

  7. Park JH, Palomba ML, Devlin SM, Valtis YK, Sikder DS, Senechal B, et al. A phase I study of CD19-Targeted 19(T2)28z1xx CAR T cells in adult patients with relapsed or refractory diffuse large B-Cell lymphoma. Blood. 2023;142(Supplement 1):892.

    Article  Google Scholar 

  8. Zheng B, Hu Y, Zhang J, Zhang M, Li W, Wu W, et al. Long Term follow-up results of Brl-201 phase I study, a Crispr-based non-viral PD-1 Locus Specific Integrated Anti-CD19 CAR-T cells in treating relapsed or refractory Non-hodgkin’s lymphoma. Blood. 2023;142(Supplement 1):2108.

    Article  Google Scholar 

  9. Abramson JS, Ramakrishnan A, Pierola AA, Braunschweig I, Cartron G, Thieblemont C, et al. Preliminary Results of Nathali-01: A First-in-Human Phase I/IIa Study of UCART20x22, a Dual Allogeneic CAR-T Cell Product Targeting CD20 and CD22, in Relapsed or Refractory (R/R) Non-Hodgkin Lymphoma (NHL). Blood. 2023;142(Supplement 1):2110.

    Article  Google Scholar 

  10. Tu S, Zhou L, Huang R, Zhou X, Yang J, Li M, et al. Efficacy and Safety of Chimeric Antigen Receptor T Cells Therapy Strategy with Dual Targeting of CD19 and CD70 to treat Relapsed/Refractory diffuse large B-Cell lymphoma. Blood. 2023;142(Supplement 1):3492.

    Article  Google Scholar 

  11. Li P, Yu W-J, Zhou L, Yang M, Ye S, Zhu J, et al. C-CAR039, a Novel Anti-CD20/CD19 bi-specific CAR T-Cell therapy shows deep and durable clinical benefits in patients with relapsed or refractory (r/r) B-Cell Non-hodgkin Lymphoma (B-NHL) in Long Term follow up. Blood. 2023;142(Supplement 1):1025.

    Article  Google Scholar 

  12. Wang ML, Frigault MJ, Yazji S, Katz Y, Robinson J, Breitmeyer JB, et al. Trial-in-Progress: a phase 1/2 Multi-center Study of Onct-808, a ROR1-Specific CAR T, in adult patients with Relapsed/Refractory aggressive B cell lymphoma. Blood. 2023;142(Supplement 1):4857.

    Article  Google Scholar 

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This work was financially supported by National Natural Science Foundation of China (No. 82270175), Natural Science Foundation of Fujian Province of China (2021J02040), Joint Funds for the Innovation of Science and Technology of Fujian Province (2023Y9173), National Key Clinical Specialty Discipline Construction Program (2021-76) and Fujian Provincial Clinical Research Center for Hematological Malignancies (2020Y2006).

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ZX and HL designed the study. WZ and SL drafted the manuscript. JL, SX and MW prepared the tables. All authors participated in the process of drafting and revising the manuscript. All authors read and approved the final manuscript.

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Correspondence to Han Liu or Zhenshu Xu.

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Zhang, W., Li, S., Long, J. et al. Novel CAR T-cell therapies for relapsed/refractory B-cell malignancies: latest updates from 2023 ASH annual meeting. Exp Hematol Oncol 13, 43 (2024).

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