Modular Chimeric Antigen Receptor Systems for Universal CAR T Cell Retargeting

Sutherland, Ashley R.; Owens, Madeline N; Geyer, C. Ronald

doi:10.3390/ijms21197222

Cited by 29 publications

(39 citation statements)

References 48 publications

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“…The CAR is split into two parts: (i) the signaling module on T cells, consisting of the extracellular domain that specifically binds to the switching module and the intracellular domain that transmits the activation signals; (ii) the switching module, usually a bispecific antibody or small molecule recognized by the signaling module on T cells and binding to the targets on cancer cells. This split, universal, and programmable (SUPRA) CAR system currently adopts a variety of recognition modes including neo-epitopes, SpyTag, biotin, and fluorescein isothiocyanate (FITC) and leucine zippers (40). Clinical trials of SUPRA CAR have been carried out for CD19/ CD20 (NCT02776813) and CD123 (NCT04230265).…”

Section: Modularization and Logic Gatingmentioning

confidence: 99%

Advances in Universal CAR-T Cell Therapy

Lin

Cheng

et al. 2021

Front. Immunol.

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Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy.

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Section: Modularization and Logic Gatingmentioning

confidence: 99%

Advances in Universal CAR-T Cell Therapy

Lin

Cheng

et al. 2021

Front. Immunol.

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“…The system provides versatile ON/OFF-switch possibilities as well as combinatorial Boolean logic responses by tuning zipper motif affinity and scFv specificity. A substantial number of studies exploiting the modular potential of soluble antibodies with universal CARs is emerging [ 148 , 149 , 150 ] and will therefore not be further detailed here, since a comprehensive review has recently been published [ 151 ]. Of note, the above-mentioned systems solely rely on an antibody fragment that, in a near-cell environment, binds the extracellular CAR domain without additional control.…”

Section: Modulating Car Specificitymentioning

confidence: 99%

Pharmacologic Control of CAR T Cells

Caulier

Enserink

Wälchli

2021

IJMS

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Chimeric antigen receptor (CAR) therapy is a promising modality for the treatment of advanced cancers that are otherwise incurable. During the last decade, different centers worldwide have tested the anti-CD19 CAR T cells and shown clinical benefits in the treatment of B cell tumors. However, despite these encouraging results, CAR treatment has also been found to lead to serious side effects and capricious response profiles in patients. In addition, the CD19 CAR success has been difficult to reproduce for other types of malignancy. The appearance of resistant tumor variants, the lack of antigen specificity, and the occurrence of severe adverse effects due to over-stimulation of the therapeutic cells have been identified as the major impediments. This has motivated a growing interest in developing strategies to overcome these hurdles through CAR control. Among them, the combination of small molecules and approved drugs with CAR T cells has been investigated. These have been exploited to induce a synergistic anti-cancer effect but also to control the presence of the CAR T cells or tune the therapeutic activity. In the present review, we discuss opportunistic and rational approaches involving drugs featuring anti-cancer efficacy and CAR-adjustable effect.

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“…The tagged targeting domain acts as a switchable adaptor element, and the signalling module is integrated into the modular CAR T cell main body. When competent, the adaptor elements are connected to the signalling module through the interaction between the switch element and the receptor [30]. The connection forms an integral and functional CAR structure and allows the T cell to activate its killing activities.…”

Section: Modular Car Systems' Structurementioning

confidence: 99%

“…Figure 1: This demonstrates the structural difference between the conventional CAR and modular CAR system. The significant difference is the split design of the modular CAR system [30]. (A) Conventional CAR structure consists of scFv targeting TAAs and T cell signalling domain to activate the anti-tumor activities.…”

Section: Modular Car Systems' Structurementioning

confidence: 99%

“…For the modular CAR systems, TAA targeting elements that could be tagged with a suitable switch element has the potential to be a working adaptor. Researchers have demonstrated the use of antigen-binding fragments (Fabs), nanobodies, and full-length immunoglobulin (IgG) in modular CAR systems [30]. Small biomolecules like folate have also been demonstrated to be incorporated into modular CAR systems targeting unconventional biomarkers [33].…”

Section: Expand the Use Of Targeting Elementsmentioning

confidence: 99%

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Universal CAR T cell: engineering of universal T cell, modular CAR system, and applications

Duan¹,

Lin²,

Zhou³

2021

2021 International Conference on Medical Imaging, Sanitation and Biological Pharmacy (MISBP 2021)

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Universal Chimeric Antigen Receptor T cells (CAR T), an alternative design based on conventional CAR T cells, uses a switchable adaptor for a better redirection towards the target site. This technology overcomes the obstacles of the conventional Car T cells system, such as immunogenicity, massive expression of cytokine and fixed antigen specificity. This article introduces universal CAR T cells from both the perspectives of the universal T cells and its modular CAR systems, illustrating the advancement of universal CAR T cells to overcome the limitation of conventional CAR T cells and serve as a more controllable and highly promising system. The universal CAR T cells section focuses on the challenges of choosing T cell sources and the corresponding solutions, while the modular CAR system section summarizes the different types of switchable adaptors in combination with clinical applications in various types of cancer treatments. Overall, universal CAR T cells therapy is a novel development that not only out-competes but also recovers the shortage of the conventional CAR T cells system. With the use of switchable adaptors, the universal CAR T cells system is commercially beneficial for the public and a safe product to allow the industry to expand the clinical application of different types of cancers.

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Modular Chimeric Antigen Receptor Systems for Universal CAR T Cell Retargeting

Cited by 29 publications

References 48 publications

Advances in Universal CAR-T Cell Therapy

Advances in Universal CAR-T Cell Therapy

Pharmacologic Control of CAR T Cells

Universal CAR T cell: engineering of universal T cell, modular CAR system, and applications

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