ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells

Guedan, Sonia; Chen, Xi; Madar, Aviv; Carpenito, Carmine; McGettigan, Shannon E.; Frigault, Matthew J.; Lee, Ji‐Hyun; Posey, Avery D.; Scholler, John; Scholler, Nathalie; Bonneau, Richard; June, Carl H.

doi:10.1182/blood-2013-10-535245

Cited by 278 publications

(232 citation statements)

References 40 publications

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“…In addition to direct administration to patients, inhibitors can be used during in vitro expansion of cells for adoptive cell transfer therapies to improve the functional stability of T cells after transfer into patients 179 . With the advent of chimeric antigen receptor (CAR) technologies to redirect cytotoxic T cells to specific antigenic targets comes the potential to engineer CARs that are linked to different intracellular signalling domains that promote distinct functions in CD4 + T cells 180,181 .…”

Section: Bet Inhibitorsmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Section: Bet Inhibitorsmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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“…In the context of adoptive immunotherapy, ICOS signaling enhances the antitumor activity of human and murine Th17 cells and Tc17 cells (9,51). Moreover, introducing the ICOS domain into CARs enhanced cellular engraftment in vivo (52)(53)(54). In light of our work, we suspect that combining drugs or genetic strategies to regulate p110δ and β-catenin induced in T cells could augment various forms of cancer immunotherapy, including cytokine therapy, checkpoint modulators, and cellular therapy.…”

Section: Discussionmentioning

confidence: 99%

β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity

Majchrzak¹,

Nelson²,

Bowers³

et al. 2017

JCI Insight

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“…14,15 In addition to CD28 and 4-1BB, other co-stimulatory molecules, such as ICOS, OX-40, CD40, and CD27, have been tested in multiple pre-clinical model. 16–19 Previously, we determined that co-stimulation of toll-like receptor 2 can potentiate the anti-tumor efficacy of CAR-T cell. 20 Together, these findings demonstrate the importance of optimizing the co-stimulatory molecules in CAR-T cells.…”

Section: Introductionmentioning

confidence: 99%

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

et al. 2018

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Chimeric antigen receptor (CAR) T cell immunotherapies have shown remarkable efficacy in treating multiple types of hematological malignancies but are not sufficiently effective at treating solid tumors. NKG2D is a strong activating receptor for NK cells and a co-stimulatory receptor for T cells. NKG2D signal transduction depends on DNAX-activating protein 10 (DAP10). Here, we introduced the cytoplasmic domain of DAP10 into the second-generation CARs M28z and G28z to generate M28z10 and G28z10, which target mesothelin (MSLN) and glypican 3 (GPC3), respectively. T cells expressing M28z10 or G28z10 showed enhanced and prolonged effector function against MSLN+ lung cancer or GPC3+ hepatocellular carcinoma cell lines in culture and secreted elevated levels of cytokines, including IL-2, IFN-γ, granzyme B, and GM-CSF. In addition, M28z10 CAR-T cells showed greater anti-tumor activity than those expressing M28z in both A549 cell line xenografts and human lung cancer patient-derived xenografts (PDX). Similarly, G28z10 exhibited higher efficacy in causing tumor regression than did G28z in hepatocellular carcinoma PDX. Therefore, our results show that DAP10 signaling contributes to the function of CAR-T cells in both lung cancer and hepatocellular carcinoma and can enhance the efficacy of CAR-T cells.

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ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells

Abstract: Key Points ICOS-based CARs program bipolar TH17/TH1 cells with augmented effector function and in vivo persistence. The expression of selected CAR endodomains can program T cells for their subsequent differentiation fates and effector functions.

Cited by 278 publications

References 40 publications

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

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