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Dual-targeted CAR T-cell immunotherapies for hematological malignancies: latest updates from the 2023 ASH annual meeting


Over the past few years, dual-targeted chimeric antigen receptor (CAR) T-cell therapy has been employed in the management of hematological malignancies to mitigate treatment failure, particularly in cases of antigen escape. The most widely used approaches include CD19/CD20, CD20/CD22, and BCMA/CD19 CAR T-cells. Alternative immune cells, including natural killer T cells and invariant natural killer T cells, exhibit innate anti-tumor activity and reduced toxicity. This review summarizes several recent clinical trial reports and preclinical studies from the 2023 American Society of Hematology (ASH) annual meeting on dual-targeted CAR T-cell immunotherapy for hematological malignancies.

To the editor

Although single-targeted chimeric antigen receptor (CAR) T cells have achieved remarkable success in treating hematological malignancies, relapse remains a major obstacle to achieving long-term survival [1]. CAR T cells targeting multiple antigens have been demonstrated to be an effective strategy to overcome antigen escape [2]. Here, we summarize the latest reports on dual-targeted CAR T-cell immunotherapy for hematological malignancies from the 2023 American Society of Hematology (ASH) annual meeting.

Dual-targeted CAR T-cell therapies for B-NHL

Three trials reported the outcomes of CD19/CD20 CAR T-cell therapy for relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL) [3,4,5]. Eleven r/r B-NHL patients (pts) received CART19/20 therapy derived from autologous naïve/memory T cells (Table 1) [3]. The overall objective rate (ORR) was 90.9% and the complete response (CR) rate was 72.7% (Table 2). With a median follow-up (mFU) of 32.3 months, the median progression-free survival (mPFS) and median overall survival (mOS) were not reached. Six pts experienced grade 1 cytokine release syndrome (CRS). No immune effector cell-associated neurotoxicity syndrome (ICANS) occurred.

LV20.19 CAR T cells, which also target CD20/CD19, are enriched for stem cell-like memory and central memory T cells (Table 1) [4]. A total of 17 pts with r/r mantle cell lymphoma (MCL) were enrolled, resulting in 100% ORR and 76% CR (Table 2). Two pts relapsed at 8 and 24 months, respectively. The 1-year PFS rate was 77%, and the 1-year OS rate was 84%. Two pts developed grade 3 ICANS. No severe CRS (grade ≥ 3) was observed.

C-CAR039, an autologous CD19/CD20 CAR T-cell therapy, was administered to r/r B-NHL pts resistant to CD20 antibody (Table 1) [5]. In total 91.5% of pts (43/47) achieved ORR, with 85.1% (40/47) achieving CR (Table 2). With a mFU of 23.9 months, the estimated 2-year PFS and OS were 66.0% and 77.9%, respectively. Only one patient experienced grade 3 CRS. No severe ICANS occurred.

ATA3431, an allogeneic CD19/CD20 CAR T-cell product, demonstrated enhanced persistence and superior anti-tumor activity in a mouse model of Burkitt’s lymphoma (Table 1) [6].

API-192, targeting CD19 and CD20, is a cord blood CD34 hematopoietic stem and progenitor cell-derived natural killer T (NKT) cell product armored with IL-15 (Table 1) [7]. API-192 exhibited robust expansion and serial tumor killing against Raji and Nalm6 cells.

UCART20 × 22 is the first human allogeneic CD20/CD22 CAR T-cell product (Table 1) [8]. All three r/r B-NHL pts treated with UCART20 × 22 demonstrated an objective response with two achieving CR. No ICANS, graft-versus-host disease (GvHD) or severe CRS occurred (Table 2).

Eight pts with r/r diffuse large B-cell lymphoma (DLBCL) were enrolled in the treatment of CD19/CD70 CAR T-cell therapy (Table 1) [9]. ORR was achieved in 87.5% of pts, with 75.0% evaluated as CR (Table 2). With a mFU of 19.9 months, three pts relapsed. The median disease-free survival (mDFS) was 10.5 months. Severe CRS or ICANS was not observed.

Dual-targeted CAR T-cell therapies for ALL

Invariant natural killer T (iNKT) cells possess the ability to safeguard against GvHD without TCR deletion (Table 1). Allogeneic CD19/CD133 CAR iNKT-cell therapy exhibited remarkable efficacy in treating MLL-rearranged acute lymphoblastic leukemia (ALL), while also potentially preventing immune escape, leptomeningeal disease, and lineage switch [10].

Dual-targeted CAR T-cell therapies for MM

A phase I clinical trial reported updated results of BCMA/CD19 CAR T-cell therapy (GC012F) for pts with newly diagnosed multiple myeloma (MM) (Table 1) [11]. The ORR was 100% and the stringent CR rate was 95.5% (Table 2). The mOS and mPFS were not reached with a mFU of 13.6 months. No ICANS or severe CRS was reported.

Dual-targeted CAR T-cell therapies for AML

CLEC12a/TIM3 CAR T cells demonstrated potent anti-leukemic efficacy and exhibited prolonged persistence in the blood for 20 weeks following administration in an acute myeloid leukemia (AML) mouse model [12].

In summary, dual-targeted CAR T-cell immunotherapies have shown promising outcomes. Severe CRS or ICANS have not been reported in most clinical trials. Larger phase II trials with extended follow-up are necessary to determine whether these approaches can mitigate the risk of antigen loss/dim, relapse, and enhance the duration of response (DOR). Furthermore, dual-targeted immunotherapies derived from allogeneic NKT or iNKT cells have demonstrated the feasibility, potency, and safety necessary for further clinical validation.

Table 1 The properties of dual-targeted CAR T cells :
Table 2 Outcomes of clinical trials of dual-targeted CAR T-cell immunotherapies in hematological malignancies from ASH 2023

Data availability

No datasets were generated or analysed during the current study.



American Society of Hematology


Acute lymphoblastic leukemia


Acute myeloid leukemia


B-cell non-Hodgkin lymphoma


Chimeric antigen receptor


Complete response


Cytokine release syndrome


Diffuse large B-cell lymphoma


Duration of response


Graft-versus-host disease


Immune effector cell-associated neurotoxicity syndrome


Invariant natural killer T


Mantle cell lymphoma


Multiple myeloma


Median disease-free survival


Median follow-up


Median overall survival


Median progression-free survival


Not available


Newly diagnosed


Natural killer T


Not reached


Overall objective rate




Relapsed or refractory


Central memory T


Naïve/memory T


Stem cell-like memory T


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The study is supported by Henan Provincial Technology Research Project (No. 222102310138).

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ZKS and SYP designed this study. YJY wrote the original manuscript. GH and HL prepared tables. All the authors participated in evaluating and editing the manuscript. The final manuscript has been read and approved by all the authors.

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Correspondence to Yongping Song or Keshu Zhou.

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Yang, J., Guo, H., Han, L. et al. Dual-targeted CAR T-cell immunotherapies for hematological malignancies: latest updates from the 2023 ASH annual meeting. Exp Hematol Oncol 13, 25 (2024).

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