Size-dependent activation of CAR-T cells

Xiao, Qian; Zhang, Xinyan; Tu, Liqun; Cao, Jian; Hinrichs, Christian S.; Su, Xiaolei

doi:10.1126/sciimmunol.abl3995

Cited by 67 publications

(43 citation statements)

References 74 publications

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“…Our results are, however, compatible with conformational changes induced by mechanical pulling forces, as well as models that do not require conformational change, such as the kinetic segregation model, which postulates that ligand binding segregates NTRs from inhibitory tyrosine phosphatases ( 73 ). Indeed, a recent study strongly suggests that CARs trigger using the kinetic segregation mechanism ( 76 ).…”

Section: Discussionmentioning

confidence: 99%

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

Burton

Siller-Farfán

Pettmann

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Chimeric antigen receptors (CARs) can redirect 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 T cell receptor (TCR) when antigen is presented on antigen-presenting cells (APCs) but nearly identical sensitivity when antigen is presented as purified protein. We next systematically measured the impact of engaging important T cell accessory receptors (CD2, LFA-1, CD28, CD27, and 4-1BB) on antigen sensitivity by adding their purified ligands. Unexpectedly, we found that engaging CD2 or LFA-1 improved the antigen sensitivity of the TCR by 125- and 22-fold, respectively, but improved CAR sensitivity by only < 5-fold. This differential effect of CD2 and LFA-1 engagement on the TCR vs. CAR was confirmed using APCs. We found that sensitivity to antigen can be partially restored by fusing the CAR variable domains to the TCR CD3 ε subunit (also known as a TRuC) and fully restored by exchanging the TCR α β variable domains for those of the CAR (also known as STAR or HIT). Importantly, these improvements in TRuC and STAR/HIT sensitivity can be predicted by their enhanced ability to exploit CD2 and LFA-1. These findings demonstrate that the CAR sensitivity defect is a result of their inefficient exploitation of accessory receptors and suggest approaches to increase sensitivity.

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Section: Discussionmentioning

confidence: 99%

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

Burton

Siller-Farfán

Pettmann

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…These data indicate that OTOT is potentially influenced by a myriad of factors, including the number of transfused cells, antigen expression densities on both the tumour and non-malignant tissues, CAR design, and the mode of administration 17,23,44,61 . 167 , an immune synapse is formed, followed by CAR T cell activation. Subsequently, cytotoxic granules containing perforin and granzymes are released, with the latter entering the target cell via perforin channels, triggering intrinsic apoptosis by damaging mitochondria and activating caspases 28,30 .…”

Section: Review Articlementioning

confidence: 99%

“…Fig. 2 | CAR T cell cytolytic mechanisms and paracrine effects.Upon recognition of a tumour-associated antigen (TAA) by a chimeric antigen receptor (CAR) T cell167 , an immune synapse is formed, followed by CAR T cell activation. Subsequently, cytotoxic granules containing perforin and granzymes are released, with the latter entering the target cell via perforin channels, triggering intrinsic apoptosis by damaging mitochondria and activating caspases28,30 .…”

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confidence: 99%

Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

et al. 2022

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Therapies with genetically modified T cells that express chimeric antigen receptors (CARs) specific for CD19 or B cell maturation antigen (BCMA) are approved to treat certain B cell malignancies. However, translating these successes into treatments for patients with solid tumours presents various challenges, including the risk of clinically serious on-target, off-tumour toxicity (OTOT) owing to CAR T cellmediated cytotoxicity against non-malignant tissues expressing the target antigen. Indeed, severe OTOT has been observed in various CAR Review articlewe examine the implications of OTOT on the development of CAR T cell therapies targeting solid tumours, summarize OTOT evidence in preclinical and clinical studies, and discuss advances in CAR T cell engineering that might help to overcome OTOT in the clinic. Risks and mechanisms of OTOTOTOT stems from CAR T cell-mediated recognition and lysis of nonmalignant tissues expressing the target antigen, potentially causing severe adverse events 23,26 . Upon recognition of a target antigen, CAR T cell activation leads to the formation of an immune synapse between the CAR and the target cell 27 , triggering effector functions (Fig. 2). The release of perforin and granzymes 28 is assumed to be a principal mechanism of CAR T cell-mediated cytotoxicity. However, other mechanisms, such as upregulation of T cell-surface molecules to induce target apoptosis (such as FAS ligand) 29 or secretion of cytokines, including IFNγ and/or TNF, may also contribute to tissue destruction [29][30][31] (Fig. 2).To generate CAR T cells that are both safe and effective in patients with solid tumours, target antigen selection is crucial. Optimal antigen candidates, referred to as neoantigens, should be exclusively expressed on malignant cells and not on non-malignant cells. Such antigens could arise from tumour-specific non-synonymous mutations, insertions or deletions that alter the amino acid sequence of cell-surface proteins, aberrant expression of oncofetal antigens, or tumour-specific posttranslational modifications [32][33][34][35][36][37] . However, cell-surface neoantigens are rare, particularly in tumours with a low mutational burden 38 . EGFRvIII, found in 24-67% of glioblastomas, is one of the few identified examples 39,40 . Consequently, the majority of CAR T cell therapy targets for solid tumours are tumour-associated antigens (TAAs) that are also expressed on non-malignant tissues (Fig. 3).

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“…The spatial boundary of the immune synapse is approximately 15 nm. According to the segregation model of T cell activation, use of a proper hinge size (<15 nm) of CAR-T cells efficiently excludes the negative regulator of phosphatase CD45 from the non-classical immune synapse before antigen-dependent phosphorylation signals are transmitted by kinases [73,74]. Although the CD8α hinge resists hinge proteolysis, modification of the hinge length (39 amino acids) decreases the treatment-associated adverse effects of Tis-cel with 19BBζ (71) CAR-T cells.…”

Section: Reviewmentioning

confidence: 99%

T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma

Luan¹,

Deng²

2023

Hematology and Oncology Discovery

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Refractory and/or relapsed (r/r) diffuse large B-cell lymphomas after treatment with two lines of systemic chemoimmunotherapy exhibit diversity in genetics, tissue biology, and pathology, as well as poor prognosis. Patient TCRαβ cells engineered with a CD19-specific chimeric antigen receptor (CAR) have shown promising clinical outcomes in r/r diffuse large B-cell lymphoma. The ZUMA-1 study, the JULIET study, and the TRANSCEND NHL 001 study of three prototype 19CAR-T cells have indicated an overall response rate of 52–82%, a complete response rate of 40–58%, and a 12-month progression-free survival of 33.2%–46.6%, with clinically manageable treatment related toxicity. At the 5-year follow-up, relapse was observed in approximately 57% of patients within 1 year. Understanding of the risk factors for non-response remains insufficient. In addition to intrinsic tumor resistance, such as aberrant apoptotic signaling, downregulation or loss of tumor-associated antigens (TAA), an immunosuppressive tumor microenvironment, and CAR-T cell exhaustion in vivo have been suggested to be important risk factors. Mechanisms underlying 19CAR-T cell exhaustion under chronic TAA exposure, and limited 19CAR-T cell trafficking and infiltration into the tumor mass have been reported. Moreover, tumor escape in the presence of low TAA density remains a challenge in 1928ζ CAR-T cell treatment. In this review, we provide an overview of modified modular CAR elements and their synergistic effects in controlling T-cell function. We then briefly discuss novel strategies against tumors with low TAA density, such as bispecific tandem or loop CAR recognition domains, the development of human leukocyte antigen-independent synthetic TCRαβ double-chain receptors integrated into the constant region of the TCRα chain, and armored CAR-T cells targeting the tumor microenvironment.

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Size-dependent activation of CAR-T cells

Cited by 67 publications

References 74 publications

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

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

Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma

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