THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells

Sun, Chuang; Shou, Peishun; Du, Hongwei; Hirabayashi, Koichi; Chen, Yuhui; Herring, Laura E.; Ahn, Sarah; Xu, Yingxin; Suzuki, Kyogo; Li, Guangming; Tsahouridis, Ourania; Su, Lishan; Savoldo, Barbara; Dotti, Gianpietro

doi:10.1016/j.ccell.2019.12.014

Cited by 101 publications

(104 citation statements)

References 42 publications

(48 reference statements)

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“…The distal PYAP subdomain initiates signaling by binding LCK (20,21), which has been confirmed in CARs (11,22).…”

Section: Introductionmentioning

confidence: 81%

“…Similarly, LCK-mediated signaling is critical for CAR T cells with a CD8 transmembrane domain (11), and recruitment of LCK to the CAR synapse can enhance tumor killing in 4-1BB CARs (22). Ultimately, these mutations will be best evaluated in patients to determine how they impact clinical outcomes.…”

Section: Mut06 Has Reduced Exhaustion-related Gene Expression and Accmentioning

confidence: 99%

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CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function

Boucher

Kotani

et al. 2021

Cancer Immunology Research

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An obstacle to the development of chimeric antigen receptor (CAR) T cells is the limited understanding of CAR T-cell biology and the mechanisms behind their antitumor activity. We and others have shown that CARs with a CD28 costimulatory domain drive high T-cell activation, which leads to exhaustion and shortened persistence. This work led us to hypothesize that by incorporating null mutations of CD28 subdomains (YMNM, PRRP, or PYAP), we could optimize CAR T-cell costimulation and enhance function. In vivo, we found that mice given CAR T cells with only a PYAP CD28 endodomain had a significant survival advantage, with 100% of mice alive after 62 days compared with 50% for mice with an unmutated endodomain. We observed that mutant CAR T cells remained more sensitive to antigen after ex vivo antigen and PD-L1 stimulation, as demonstrated by increased cytokine production. The mutant CAR T cells also had a reduction of exhaustion-related transcription factors and genes such as Nfatc1, Nr42a, and Pdcd1. Our results demonstrated that CAR T cells with a mutant CD28 endodomain have better survival and function. This work allows for the development of enhanced CAR T-cell therapies by optimizing CAR T-cell costimulation.

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“…The distal PYAP subdomain initiates signaling by binding LCK (20,21), which has been confirmed in CARs (11,22).…”

Section: Introductionmentioning

confidence: 81%

Section: Mut06 Has Reduced Exhaustion-related Gene Expression and Accmentioning

confidence: 99%

CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function

Boucher

Kotani

et al. 2021

Cancer Immunology Research

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“…In a humanized mouse model, they demonstrated that this design effectively suppressed tumor growth without significant weight loss of the mice. The reduced cytokine release in the plasma after AP21967 administration indicated that toxicities such as CRS could be ameliorated by this strategy (55). Therefore, the cytotoxicity of CAR-T cells can be precisely controlled by small molecules to prevent possible severe side effects.…”

Section: Modifying Downstream Signaling Of Cd28ζ Carmentioning

confidence: 99%

Engineering Cytoplasmic Signaling of CD28ζ CARs for Improved Therapeutic Functions

et al. 2020

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Chimeric antigen receptor modified T cells (CAR-T) have yielded impressive clinical outcomes in treating hematopoietic malignancies. However, relapses have occurred in a substantial number of patients and limited the development of CART therapy. Most underlying reasons for these relapses can be attributed to poor persistence and rapid exhaustion of CART cells in vivo. Despite multiple strategies having been developed, how to improve CART persistence or resist exhaustion while maintaining sufficient cytotoxic functions is still a great challenge. Here we discuss engineering cytoplasmic signaling as an important strategy for CAR optimization. This review summarizes recent advances showing that the anti-tumor function of CART cells can be improved by optimizing the CD3ζ domain or downstream signaling of CD28ζ CAR.

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“…Only very recently have the molecular mechanisms underpinning these functional differences begun to be systematically dissected. By comparing signaling downstream of CD28 and 4-1BB tail sequences in the context of otherwise identical CD19 CARs, one study [ 176 ] found that enhanced Lck recruitment amplifies both basal and antigen-induced phosphorylation in the CD28-containing CAR, while the unique ability to recruit phosphatase SHP1 (in a THEMIS-SHP1 complex) suppresses basal phosphorylation and attenuates antigen-induced phosphorylation in the 4-1BB-containing CAR. Importantly, the authors went on to show that engineering SHP1 recruitment into the CD28-containing CAR could ameliorate cytokine toxicity without sacrificing overall efficacy, emphasizing the utility of gaining detailed mechanistic understanding for engineering better therapies.…”

Section: Functional Consequences Of Car Design and Structurementioning

confidence: 99%

T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

Chandler

Call

2020

IJMS

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The impressive success of chimeric antigen receptor (CAR)-T cell therapies in treating advanced B-cell malignancies has spurred a frenzy of activity aimed at developing CAR-T therapies for other cancers, particularly solid tumors, and optimizing engineered T cells for maximum clinical benefit in many different disease contexts. A rapidly growing body of design work is examining every modular component of traditional single-chain CARs as well as expanding out into many new and innovative engineered immunoreceptor designs that depart from this template. New approaches to immune cell and receptor engineering are being reported with rapidly increasing frequency, and many recent high-quality reviews (including one in this special issue) provide comprehensive coverage of the history and current state of the art in CAR-T and related cellular immunotherapies. In this review, we step back to examine our current understanding of the structure-function relationships in natural and engineered lymphocyte-activating receptors, with an eye towards evaluating how well the current-generation CAR designs recapitulate the most desirable features of their natural counterparts. We identify key areas that we believe are under-studied and therefore represent opportunities to further improve our grasp of form and function in natural and engineered receptors and to rationally design better therapeutics.

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THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells

Cited by 101 publications

References 42 publications

CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function

CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function

Engineering Cytoplasmic Signaling of CD28ζ CARs for Improved Therapeutic Functions

T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

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