Efficacy and Safety of CD28- or 4-1BB-Based CD19 CAR-T Cells in B Cell Acute Lymphoblastic Leukemia

Zhao, Xiangyu; Yang, Junfang; Zhang, Xian; Lu, Xiangjun; Xiong, Min; Zhang, Jianping; Zhou, Xiaosu; Qi, Feifei; He, Ting; Ding, Yanping; Hu, Xuelian; Smet, Floris De; Lu, Peihua; Huang, Xiao‐Jun

doi:10.1016/j.omto.2020.06.016

Cited by 83 publications

(76 citation statements)

References 36 publications

(69 reference statements)

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“…The type of costimulatory ligand in CAR can greatly impact CAR T cell function and phenotype. For example, differences in phenotype between 28z and BBz have been demonstrated in animal models, which show that the 4-1BB signaling domain enhanced CAR T-cell memory development and persistence, and promoted oxidative phosphorylation and mitochondrial biogenesis, while the CD28 signaling domain pushed towards an effector phenotype and glycolysis [ 214 , 215 ]. Selecting the correct co-stimulatory domain, or combining multiple co-stimulatory domains, may therefore improve CAR T cell function.…”

Section: Possible Solutionsmentioning

confidence: 99%

Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma

Bruggen

Martens

Tonino

et al. 2020

Cancers

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The next frontier towards a cure for B-cell non-Hodgkin lymphomas (B-NHL) is autologous cellular immunotherapy such as immune checkpoint blockade (ICB), bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T-cells. While highly successful in various solid malignancies and in aggressive B-cell leukemia, this clinical success is often not matched in B-NHL. T-cell subset skewing, exhaustion, expansion of regulatory T-cell subsets, or other yet to be defined mechanisms may underlie the lack of efficacy of these treatment modalities. In this review, a systematic overview of results from clinical trials is given and is accompanied by reported data on T-cell dysfunction. From these results, we distill the underlying pathways that might be responsible for the observed differences in clinical responses towards autologous T-cell-based cellular immunotherapy modalities between diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). By integration of the clinical and biological findings, we postulate strategies that might enhance the efficacy of autologous-based cellular immunotherapy for the treatment of B-NHL.

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Section: Possible Solutionsmentioning

confidence: 99%

Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma

Bruggen

Martens

Tonino

et al. 2020

Cancers

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“…On this issue, inconsistent results have been observed across the literature. Reports showed that T cells could persist for a relatively long time after T cells infusion (45)(46)(47). On the contrary, Li et al demonstrated that CAR-T cells could exist only for 5 to 7 days after CAR-T cells transfusion (48).…”

Section: Discussionmentioning

confidence: 99%

“…On this issue, inconsistent results have been observed across the literature. Reports showed that T cells could persist for a relatively long time after T cells infusion ( 45 – 47 ). On the contrary, Li et al.…”

Section: Discussionmentioning

confidence: 99%

The Transferrin Receptor-Directed CAR for the Therapy of Hematologic Malignancies

Guo

Zhang

et al. 2021

Front. Immunol.

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As many patients ultimately relapse after chimeric antigen receptor (CAR) T-cell therapy, identification of alternative targets is currently being evaluated. Substantial research efforts are underway to develop new targets. The transferrin receptor (TfR) is prevalently expressed on rapidly proliferating tumor cells and holds the potential to be the alternative target. In order to investigate the efficacy and challenges of TfR-targeting on the CAR-based therapy strategy, we generated a TfR-specific CAR and established the TfR-CAR–modified T cells. To take the advantage of TfR being widely shared by multiple tumors, TfR-CAR T cells were assessed against several TfR+ hematological malignant cell lines. Data showed that TfR-CAR T cells were powerfully potent in killing all these types of cells in vitro and in killing T-ALL cells in vivo. These findings suggest that TfR could be a universal target to broaden and improve the therapeutic efficacy of CAR T cells and warrant further efforts to use these cells as an alternative CAR T cell product for the therapy of hematological malignancies.

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“…Except for scFv clone selection, CAR structure considerations, especially costimulation region design, also affect CAR‐T cell response. Several preclinical studies and a few clinical trial results suggest that CAR‐T cells incorporating the 4‐1BB costimulatory domain may have better persistence compared with those involving the CD28 costimulatory domain (Kawalekar et al, 2016; Long et al, 2015; Milone et al, 2009; Philipson et al, 2020; Ying et al, 2019; Zhao et al, 2020). In this case, we performed a detailed comparison of Clone 78‐BBz CAR and FMC63‐BBz CAR from different aspects, which suggested that Clone 78‐BBz CAR‐T cells possess a function comparable with that of FMC63‐BBz CAR‐T cells in vitro or in murine models.…”

Section: Discussionmentioning

confidence: 99%

Development and functional characterization of novel fully human anti‐CD19 chimeric antigen receptors for T‐cell therapy

Dai

Jia³

et al. 2021

Journal Cellular Physiology

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Impressive outcomes have been achieved by chimeric antigen receptor (CAR)‐T cell therapy using murine‐derived single‐chain variable fragment (scFv) FMC63 specific for CD19 in patients with B cell malignancies. However, evidence suggests that human anti‐mouse immune responses might be responsible for poor persistence and dysfunction of CAR‐T cells, leading to poor outcomes or early tumor recurrence. Substituting a fully human scFv for murine‐derived scFv may address this clinically relevant concern. In this study, we discovered two human anti‐CD19 scFv candidates through an optimized protein/cell alternative panning strategy and evaluated their function in CAR‐T cells and CD19/CD3 bispecific antibody formats. The two clones exhibited excellent cytotoxicity in CAR‐T cells and bispecific antibodies in vitro compared with the benchmarks FMC63 CAR‐T cells and blinatumomab. Furthermore, Clone 78‐BBz CAR‐T cells exhibited similar in vivo antitumor activity to FMC63‐BBz CAR‐T cells. Our results indicate that Clone 78‐BBz CAR has excellent efficacy and safety profile and is a good candidate for clinical development.

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Efficacy and Safety of CD28- or 4-1BB-Based CD19 CAR-T Cells in B Cell Acute Lymphoblastic Leukemia

Cited by 83 publications

References 36 publications

Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma

Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma

The Transferrin Receptor-Directed CAR for the Therapy of Hematologic Malignancies

Development and functional characterization of novel fully human anti‐CD19 chimeric antigen receptors for T‐cell therapy

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