Driving better and safer HER2-specific CARs for cancer therapy

Liu, Xianqiang; Zhang, Nan; Shi, Huan

doi:10.18632/oncotarget.17528

Cited by 48 publications

(41 citation statements)

References 104 publications

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“…where modulating receptor sensitivity through the selection of variable-affinity HER2-binding scFvs (Liu et al, 2015(Liu et al, , 2017 facilitated the production of CAR-T cells that were responsive to HER2-high tumour cells but not to healthy tissues expressing lower levels of the antigen. Unlike the complex processes of mutating and selecting variable-affinity antigen-binding domains or empirically testing combinatorial multi-domain modifications in different CAR formats, the proCAR platform has the potential to be easily implemented on the background of any existing single-chain CAR designs and combined with other modifications to extracellular or intracellular sequences.…”

Section: Discussionmentioning

confidence: 99%

De novo designed transmembrane domains tune engineered receptor functions

Elazar

Chandler

Davey

et al. 2020

Preprint

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De novo designed receptor transmembrane domains (TMDs) present opportunities for precise control of cellular functions. We develop a strategy for generating programmed membrane proteins (proMPs): single-pass α-helical TMDs that form oligomeric complexes through computationally defined and crystallographically validated interfaces. To demonstrate their usefulness, we program specific oligomeric interactions into a chimeric antigen receptor (to generate proCARs) and analyze the cytotoxic potency and cytokine release profiles of proCAR-T cells. We show that dimeric and trimeric proCAR-expressing T cells have significantly enhanced antitumor cytotoxicity compared to a monomeric proCAR and a reference CAR similar to those currently used in the clinic. Independently of oligomeric state, all proCAR-T cells exhibited strongly attenuated inflammatory cytokine release. These results have important implications for both safety and efficacy of cellular immunotherapies and highlight the advantages of programming precise structural features in engineered receptors through de novo protein design. The proMPs provide an exceptionally modular route to tuning receptor function and can be easily incorporated into existing CAR designs.

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Section: Discussionmentioning

confidence: 99%

De novo designed transmembrane domains tune engineered receptor functions

Elazar

Chandler

Davey

et al. 2020

Preprint

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“…The first clinical use of trastuzumab incorporated into a CAR T resulted in a serious adverse event, with the patient developing on-target, off-tumor toxicity related to the redirection of CAR T cells to lung epithelium, proving fatal [ 17 ]. Since this initial trial, many groups have investigated safer ways to target HER2, reviewed by Liu et al [ 18 ], with the modular anti-FITC CAR T technology, a contender to address the safety issues with targeting this cancer-associated antigen.…”

Section: Modular Car T Platformsmentioning

confidence: 99%

Modular Chimeric Antigen Receptor Systems for Universal CAR T Cell Retargeting

Sutherland

Owens

Geyer

2020

IJMS

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The engineering of T cells through expression of chimeric antigen receptors (CARs) against tumor-associated antigens (TAAs) has shown significant potential for use as an anti-cancer therapeutic. The development of strategies for flexible and modular CAR T systems is accelerating, allowing for multiple antigen targeting, precise programming, and adaptable solutions in the field of cellular immunotherapy. Moving beyond the fixed antigen specificity of traditional CAR T systems, the modular CAR T technology splits the T cell signaling domains and the targeting elements through use of a switch molecule. The activity of CAR T cells depends on the presence of the switch, offering dose-titratable response and precise control over CAR T cells. In this review, we summarize developments in universal or modular CAR T strategies that expand on current CAR T systems and open the door for more customizable T cell activity.

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“…This is commonly observed in CD19 CAR T cell therapies ( 60 ). Since HER antigen is expressed by cardiac and pulmonary epithelial cells, HER2 CAR T cells applied for breast cancer can exhibit cardiopulmonary toxicity ( 48 ). Based on a case report in 2010, ERBB2 CAR T cell therapy for colorectal cancer led to the death of the patient because of pulmonary toxicity ( 56 ).…”

Section: Side Effect and Toxicitymentioning

confidence: 99%

Immune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells

et al. 2018

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T cells equipped with chimeric antigen receptors (CAR T cells) have recently provided promising advances as a novel immunotherapeutic approach for cancer treatment. CAR T cell therapy has shown stunning results especially in B-cell malignancies; however, it has shown less success against solid tumors, which is more supposed to be related to the specific characteristics of the tumor microenvironment. In this review, we discuss the structure of the CAR, current clinical advantages from finished and ongoing trials, adverse effects, challenges and controversies, new engineering methods of CAR, and clinical considerations that are associated with CAR T cell therapy both in hematological malignancies and solid tumors. Also, we provide a comprehensive description of recently introduced modifications for designing smarter models of CAR T cells. Specific hurdles and problems that limit the optimal function of CAR T cells, especially on solid tumors, and possible solutions according to new modifications and generations of CAR T cells have been introduced here. We also provide information of the future directions on how to enhance engineering the next smarter generations of CAR T cells in order to decrease the adverse effects and increase the potency and efficacy of CAR T cells against cancer.

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Driving better and safer HER2-specific CARs for cancer therapy

Cited by 48 publications

References 104 publications

De novo designed transmembrane domains tune engineered receptor functions

De novo designed transmembrane domains tune engineered receptor functions

Modular Chimeric Antigen Receptor Systems for Universal CAR T Cell Retargeting

Immune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells

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