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
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Table 2 The efficacy and safety of novel CAR T-cells
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