Analysis of CAR-Mediated Tonic Signaling

Calderón, Hugo; Mamonkin, Maksim; Guedan, Sonia

doi:10.1007/978-1-0716-0146-4_17

Cited by 50 publications

(31 citation statements)

References 14 publications

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“…Sustained tonic CD3ζ phosphorylation in GD2 targeting CAR, which is triggered by antigen-independent clustering of CAR scFv, can induce early exhaustion of CAR T cells, and such tonic signaling is present to varying degrees in all CARs studied [16]. Moreover, the density of CAR surface expression which can be controlled by using different eukaryotic promoters has a substantial impact on antitumor efficacy and persistence of CAR T cells [17]. Low level expression of CARs driven by weaker rather than by stronger promoters results in significant higher numbers of circulating and tumor infiltrating CAR T cells in mice [18].…”

Section: Extracellular Structuresmentioning

confidence: 99%

Engineering better chimeric antigen receptor T cells

2020

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CD19-targeted CAR T cells therapy has shown remarkable efficacy in treatment of B cell malignancies. However, relapse of primary disease remains a major obstacle after CAR T cells therapy, and the majority of relapses present a tumor phenotype with retention of target antigen (antigen-positive relapse), which highly correlate with poor CAR T cells persistence. Therefore, study on factors and mechanisms that limit the in vivo persistence of CAR T cells is crucial for developing strategies to overcome these limitations. In this review, we summarize the rapidly developing knowledge regarding the factors that influence CAR T cells in vivo persistence and the underlying mechanisms. The factors involve the CAR constructs (extracellular structures, transmembrane and intracellular signaling domains, as well as the accessory structures), activation signaling (CAR signaling and TCR engagement), methods for in vitro culture (T cells collection, purification, activation, gene transduction and cells expansion), epigenetic regulations, tumor environment, CD4/CD8 subsets, CAR T cells differentiation and exhaustion. Of note, among these influence factors, CAR T cells differentiation and exhaustion are identified as the central part due to the fact that almost all factors eventually alter the state of cells differentiation and exhaustion. Moreover, we review the potential coping strategies aiming at these limitations throughout this study.

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Section: Extracellular Structuresmentioning

confidence: 99%

Engineering better chimeric antigen receptor T cells

2020

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“…BPs function as CAR-T engagers, with activity similar in principle to CD3-based T cell engagers (20). It was critical to demonstrate that the engager protein did not interfere with CAR T cell function by blocking antigen binding, inducing functional exhaustion through tonic signaling or triggering cell death (21,22). We used cytotoxicity assays in which the components -CAR19 T cells, BPs, and CLEC12A-positive U937 target tumor cellswere premixed in different combinations to evaluate these issues.…”

Section: The Biparatopic Bp Induces Potent Cytotoxicity In the Presence Of Car19 T Cellsmentioning

confidence: 99%

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Rennert¹,

Dufort²,

Su³

et al. 2021

Molecular Cancer Therapeutics

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Refractory Acute Myeloid Leukemia (AML) remains an incurable malignancy despite the clinical use of novel targeted therapies, new antibody-based therapies and cellular therapeutics.Here we describe the preclinical development of a novel cell therapy that targets the antigen CLEC12A with a biparatopic bridging protein. Bridging proteins are designed as "CAR-T cell engagers", with a CAR-targeted protein fused to antigen binding domains derived from antibodies. Here, we created a CD19-anti-CLEC12A bridging protein that binds to CAR19 T cells and to the antigen CLEC12A. Biparatopic targeting increases the potency of bridging protein-mediated cytotoxicity by CAR19 T cells. Using CAR19 T cells that secrete the bridging protein we demonstrate potent activity against aggressive leukemic cell lines in vivo. This CARengager platform is facile and modular, as illustrated by activity of a dual-antigen bridging protein targeting CLEC12A and CD33, designed to counter tumor heterogeneity and antigen escape, and created without the need for extensive CAR T cell genetic engineering. CAR19 T cells provide an optimal cell therapy platform with well understood inherent persistence and fitness characteristics.

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“…This therapy has resulted very effective against hematopoietic cancers, whereas it has not been very efficient against solid tumors, as CAR T cells become exhausted just like endogenous CD8 T cells responding to chronic infection or cancer [ 8 , 188 ]. To understand and possibly overcome the exhaustion program in CAR T cells, Lynn et al established a mouse HA-28z CAR T cell model generating antigen-independent tonic signaling [ 30 , 189 ]. HA-28z CAR T cells exhibited a stronger exhaustion phenotype and showed significant changes in chromatin accessibility and gene expression patterns compared with control CD19-28z CAR T cells [ 30 ].…”

Section: Regulation Of C-jun/ap-1 In Exhausted Cd8t Cells During Cmentioning

confidence: 99%

The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion

Papavassiliou

Musti

2020

Cells

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c-Jun is a major component of the dimeric transcription factor activator protein-1 (AP-1), a paradigm for transcriptional response to extracellular signaling, whose components are basic-Leucine Zipper (bZIP) transcription factors of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families. Extracellular signals regulate c-Jun/AP-1 activity at multiple levels, including transcriptional and posttranscriptional regulation of c-Jun expression and transactivity, in turn, establishing the magnitude and the duration of c-Jun/AP-1 activation. Another important level of c-Jun/AP-1 regulation is due to the capability of Jun family members to bind DNA as a heterodimer with every other member of the AP-1 family, and to interact with other classes of transcription factors, thereby acquiring the potential to integrate diverse extrinsic and intrinsic signals into combinatorial regulation of gene expression. Here, we review how these features of c-Jun/AP-1 regulation underlie the multifaceted output of c-Jun biological activity, eliciting quite distinct cellular responses, such as neoplastic transformation, differentiation and apoptosis, in different cell types. In particular, we focus on the current understanding of the role of c-Jun/AP-1 in the response of CD8 T cells to acute infection and cancer. We highlight the transcriptional and epigenetic regulatory mechanisms through which c-Jun/AP-1 participates in the productive immune response of CD8 T cells, and how its downregulation may contribute to the dysfunctional state of tumor infiltrating CD8 T cells. Additionally, we discuss recent insights pointing at c-Jun as a suitable target for immunotherapy-based combination approaches to reinvigorate anti-tumor immune functions.

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Analysis of CAR-Mediated Tonic Signaling

Cited by 50 publications

References 14 publications

Engineering better chimeric antigen receptor T cells

Engineering better chimeric antigen receptor T cells

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion

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