T cells expressing CD5/CD7 bispecific chimeric antigen receptors with fully human heavy-chain-only domains mitigate tumor antigen escape.

in Signal transduction and targeted therapy by Zhenyu Dai, Wei Mu, Ya Zhao, Jiali Cheng, Haolong Lin, Kedong Ouyang, Xiangyin Jia, Jianwei Liu, Qiaoe Wei, Meng Wang, Chaohong Liu, Taochao Tan, Jianfeng Zhou

TLDR

  • The study creates a new type of treatment called bispecific chimeric antigen receptor T-cell (CAR-T) therapy to treat refractory/relapse (r/r) T-cell leukemia/lymphoma. The study uses a special type of antibody to create a new type of CAR-T cell that can target two different proteins on T-cells. The study also adds a safety feature to the CAR-T cells. The study then tests the CAR-T cells in a lab and in animals to see how well they work. The study finds that the CAR-T cells that target two different proteins work better than the ones that only target one protein. The study also finds that the CAR-T cells with the safety feature work well and are safe. The study suggests that this new type of CAR-T therapy could be used to treat T-cell leukemia/lymphoma in people.

Abstract

Bispecific chimeric antigen receptor T-cell (CAR-T) therapies have shown promising results in clinical trials for advanced B-cell malignancies. However, it is challenging to broaden the success of bispecific CAR-T therapies to treat refractory/relapse (r/r) T-cell leukemia/lymphoma because targeting multiple T-cell-expressing antigens leads to exacerbated CAR-T cell fratricide and potential safety concerns. Fully human heavy chain variable (FHV) antibodies that specifically target CD5 or CD7 were screened and constructed to CD5/CD7 bispecific CARs. A truncated Epidermal growth factor receptor were integrated into CAR constructs to address safety concerns. To tackle the fratricidal issue of CAR-T cells targeting T-cell-pan marker(s), CRISPR/Cas9-based CD5 and CD7 genes knockout were performed before lentiviral transduction of bispecific CARs. Functional comparison between different bispecific CAR structures: tandem CARs and dual CAR were performed in vitro and in vivo to determine the optimal construct suitable for addressing T-cell malignancy antigen escape in clinical setting. Knockout of CD5 and CD7 prevents fratricide of CD5/CD7 bispecific CAR-T cells, and FHV-derived CD5/CD7 bispecific CAR-T cells demonstrate potent antitumor activity in vitro and in vivo. The fratricide-resistant FHV-derived CD5/CD7 bispecific CAR-T cells have potent antitumor activity against T-cell malignancies, and tandem CARs are more effective than dual CAR in preventing tumor escape in heterogeneous leukemic cells. The meaningful clinical efficacy and safety of tandem CD5/CD7 CAR-T cells deserve to be explored urgently.

Overview

  • The study aims to develop a bispecific chimeric antigen receptor T-cell (CAR-T) therapy targeting CD5 and CD7 antigens in refractory/relapse (r/r) T-cell leukemia/lymphoma. The study uses fully human heavy chain variable (FHV) antibodies to construct CD5/CD7 bispecific CARs. The study also integrates a truncated Epidermal growth factor receptor into CAR constructs to address safety concerns. The study performs CRISPR/Cas9-based CD5 and CD7 genes knockout before lentiviral transduction of bispecific CARs to tackle the fratricidal issue of CAR-T cells targeting T-cell-pan marker(s). The study compares the functional performance of tandem CARs and dual CARs in vitro and in vivo to determine the optimal construct suitable for addressing T-cell malignancy antigen escape in clinical settings. The study finds that tandem CARs are more effective than dual CAR in preventing tumor escape in heterogeneous leukemic cells. The study concludes that the fratricide-resistant FHV-derived CD5/CD7 bispecific CAR-T cells have potent antitumor activity against T-cell malignancies.

Comparative Analysis & Findings

  • The study compares the functional performance of tandem CARs and dual CARs in vitro and in vivo. The study finds that tandem CARs are more effective than dual CAR in preventing tumor escape in heterogeneous leukemic cells. The study concludes that tandem CARs are more effective in addressing T-cell malignancy antigen escape in clinical settings.

Implications and Future Directions

  • The study demonstrates the potential of bispecific CAR-T therapies targeting CD5 and CD7 antigens in refractory/relapse (r/r) T-cell leukemia/lymphoma. The study also addresses safety concerns associated with CAR-T cell fratricide. The study suggests that tandem CARs are more effective than dual CAR in addressing T-cell malignancy antigen escape in clinical settings. The study highlights the need for further research to explore the clinical efficacy and safety of tandem CD5/CD7 CAR-T cells.
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