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 dualtargeted CAR T-cell immunotherapy for hematological 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.
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].
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 antileukemic 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 : N/MEM , naïve/memory T; T SCM , stem cell-like memory T; T CM , central memory T; NKT, natural killer T; iNKT, invariant natural killer T; NA, not available T

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