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