Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors

Liu, Yue; Liu, Guangna; Wang, Jiasheng; Zheng, Zheyu; Jia, Lemei; Wei, Rui; Huang, Daosheng; Zhou, Zhixiao; Zhou, Liqun; Wu, Xin; Lin, Song; Zhao, Xihai; Lin, Xin

doi:10.1126/scitranslmed.abb5191

Cited by 80 publications

(79 citation statements)

References 49 publications

(65 reference statements)

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“…The incorporation of TCR-like signaling to engineered receptors has recently shown promise in multiple solid and liquid tumor models due to more controlled signaling and lower cytokine release. 20,69,70 Our data show that the TRuC platform can potentially improve the suppressive capacity of engineered Tregs in anti-drug antibody formation. The design of the next generation of antigen-specific Tregs will most likely emphasize finetuning activation in order to improve effectiveness and persistence, whereas reducing exhaustion and anergy.…”

Section: Discussionmentioning

confidence: 78%

CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII

et al. 2021

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Regulatory T cells (Tregs) control immune responses in autoimmune disease, transplantation, and enable antigen-specific tolerance induction in protein-replacement therapies. Tregs can exert a broad array of suppressive functions through their T cell receptor (TCR) in a tissue-directed and antigen-specific manner. This capacity can now be harnessed for tolerance induction by "redirecting" polyclonal Tregs to overcome low inherent precursor frequencies and simultaneously augment suppressive functions. With the use of hemophilia A as a model, we sought to engineer antigen-specific Tregs to suppress antibody formation against the soluble therapeutic protein factor (F)VIII in a major histocompatibility complex (MHC)-independent fashion. Surprisingly, high-affinity chimeric antigen receptor (CAR)-Treg engagement induced a robust effector phenotype that was distinct from the activation signature observed for endogenous thymic Tregs, which resulted in the loss of suppressive activity. Targeted mutations in the CD3z or CD28 signaling motifs or interleukin (IL)-10 overexpression were not sufficient to restore tolerance. In contrast, complexing TCR-based signaling with single-chain variable fragment (scFv) recognition to generate TCR fusion construct (TRuC)-Tregs delivered controlled antigen-specific signaling via engagement of the entire TCR complex, thereby directing functional suppression of the FVIII-specific antibody response. These data suggest that cellular therapies employing engineered receptor Tregs will require regulation of activation thresholds to maintain optimal suppressive function.

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Section: Discussionmentioning

confidence: 78%

CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII

et al. 2021

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“…The study indicates that ATM-associated DNA-damage initiation and MAPK and STAT3 signalling activation control lipid metabolism in senescent T cells in vitro. Blockade of ATM activation with the ATM-specific inhibitor, KU55933, decreased mRNA and protein expression of group IV phospholipase A 2 α in regulatory T-induced senescent T cells [ 65 ].…”

Section: Introductionmentioning

confidence: 99%

Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities

Rosell

Cardona²,

Arrieta

et al. 2021

Br J Cancer

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Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are a frequent class of driver mutations. Single EGFR tyrosine kinase inhibitor (TKI) provides substantial clinical benefit, but almost nil radiographic complete responses. Patients invariably progress, although survival can reach several years with post-treatment therapies, including EGFR TKIs, chemotherapy or other procedures. Endeavours have been clinically oriented to manage the acquisition of EGFR TKI-resistant mutations; however, basic principles on cancer evolution have not been considered in clinical trials. For years, evidence has displayed rapidly adaptive mechanisms of resistance to selective monotherapy, posing several dilemmas for the practitioner. Strict adherence to non-small cell lung cancer (NSCLC) guidelines is not always practical for addressing the clinical progression that EGFR-mutant lung adenocarcinoma patients suffer. The purpose of this review is to highlight regulatory mechanisms and signalling pathways that cause therapy-induced resistance to EGFR TKIs. It suggests combinatorial therapies that target EGFR, as well as potential mechanisms underlying EGFR-mutant NSCLC, alerting the reader to clinical opportunities that may lead to a deeper and more durable response. Molecular reprogramming contributes to EGFR TKI resistance, and the compiled information is relevant in understanding the development of new combined targeted strategies in EGFR-mutant NSCLC.

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“…Recently, it has been suggested that replacing the ζ-chain with the ε-chain of the TCR complex would improve CAR function (11,16,17). Moreover, it has been suggested that TCRlike chimeric receptors improve on the basic CAR design; by fusing the scFv directly to the extracellular domain of CD3ε (termed TruC) (18) or by replacing the variable domains of the TCR with those in the scFv (termed STAR) (19). However, accurate measurements of the relative antigen sensitivities of CARs have yet to be performed partly because it is difficult to vary the surface density of antigens on target cells.…”

Section: Introductionmentioning

confidence: 99%

Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors

Burton

Siller-Farfán

Pettmann

et al. 2021

Preprint

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Chimeric antigen receptors (CARs) can re-direct T cells to target abnormal cells but their activity is limited by a profound defect in antigen sensitivity, the source of which remains unclear. Here, we show that CARs have a >100-fold lower antigen sensitivity compared to the TCR when antigen is presented on antigen-presenting-cells, but nearly identical sensitivity when antigen is presented as purified protein in isolation. Given that the TCR uses other, accessory, receptors to achieve high sensitivity, we screened prominent accessory receptors by presenting their purified ligands together with antigen. We found that ligating the adhesion receptor CD2 or LFA-1 improved antigen sensitivity for the TCR by >100-fold, whereas for CARs the improvement was <10-fold. We reproduced these findings using target cells where the CD2 and/or LFA-1 interaction were abrogated. Sensitivity can be partially restored by fusing the CAR variable domains to the TCR CD3ε subunit (also known as a TRuC) and fully restored when exchanging the TCRαβ variable domains for those of the CAR (also known as a STAR). Our study localises the defect in CAR sensitivity to inefficient use of accessory receptors and suggests approaches to increase sensitivity.

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Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors

Cited by 80 publications

References 49 publications

CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII

CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII

Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities

Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors

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