Co-opting signalling molecules enables logic-gated control of CAR T cells

Tousley, Aidan M.; Rotiroti, Maria Caterina; Labanieh, Louai; Rysavy, Lea Wenting; Kim, Won-Ju; Lareau, Caleb A.; Sotillo, Elena; Weber, Evan W.; Rietberg, Skyler P.; Dalton, Guillermo Nicolás; Yin, Yijun; Klysz, Dorota D.; Xu, Peng; Serna, Eva L. de la; Dunn, Alexander R.; Satpathy, Ansuman T.; Mackall, Crystal L.; Majzner, Robbie G.

doi:10.1038/s41586-023-05778-2

Cited by 125 publications

(54 citation statements)

References 65 publications

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“…Extensive observations in the literature can help researchers select larger modular components to test in combinatorial designs. Tousley et al selected a small number of proteins [e.g., lymphocyte‐specific protein tyrosine kinase (Lck), Fyn, zeta chain‐associated protein kinase 70 (Zap‐70), SH2 domain‐containing leukocyte protein of 76 kDa (SLP‐76), linker for activation of T cells (LAT), and phospholipase‐C gamma 1 (PLCγ1)] involved in proximal signaling events of T‐cell activation and used them as intracellular signaling components in a new dual‐CAR system 19 . By using LAT and SLP‐76 as intracellular signaling domains, Tousley et al rationally designed a CAR that requires two antigens to activate.…”

Section: Modularity In Cell Therapymentioning

confidence: 99%

“…[10][11][12][13] Unique hinge and transmembrane domain combinations have been used to improve CAR T-cell function. [14][15][16] The CAR, chimeric costimulatory receptor (CCR), 4 synNotch, 17,18 logic-gated intracellular network chimeric antigen receptor (LINK-CAR), 19 and other proteins have been used to create therapeutic cells. These proteins can be combined with genetic regulatory elements to create gene circuits such as those used to discriminate between antigens at different densities 20 and deliver interleukin-2 (IL-2) locally to tumors.…”

Section: Modul Arit Y In Cell Ther Apymentioning

confidence: 99%

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Harnessing the power of artificial intelligence to advance cell therapy

Capponi

Daniels

2023

Immunological Reviews

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SummaryCell therapies are powerful technologies in which human cells are reprogrammed for therapeutic applications such as killing cancer cells or replacing defective cells. The technologies underlying cell therapies are increasing in effectiveness and complexity, making rational engineering of cell therapies more difficult. Creating the next generation of cell therapies will require improved experimental approaches and predictive models. Artificial intelligence (AI) and machine learning (ML) methods have revolutionized several fields in biology including genome annotation, protein structure prediction, and enzyme design. In this review, we discuss the potential of combining experimental library screens and AI to build predictive models for the development of modular cell therapy technologies. Advances in DNA synthesis and high‐throughput screening techniques enable the construction and screening of libraries of modular cell therapy constructs. AI and ML models trained on this screening data can accelerate the development of cell therapies by generating predictive models, design rules, and improved designs.

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Section: Modularity In Cell Therapymentioning

confidence: 99%

Section: Modul Arit Y In Cell Ther Apymentioning

confidence: 99%

Harnessing the power of artificial intelligence to advance cell therapy

Capponi

Daniels

2023

Immunological Reviews

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“…Co‐opting signaling molecules can enable logic‐gated control of CAR T‐cells, in which CD3ζ was replaced with intracellular proximal T‐cell signaling molecules 66 . ZAP‐70 CAR showed sufficient efficacy, while bypassing upstream signaling proteins 66 . LAT and SLP‐76, phosphorylated by ZAP‐70, were used to an engineer logic‐gated intracellular network CAR (LINK CAR) 66 …”

Section: Strategies For Controlling Car T‐cell Activitymentioning

confidence: 99%

“…ZAP‐70 CAR showed sufficient efficacy, while bypassing upstream signaling proteins 66 . LAT and SLP‐76, phosphorylated by ZAP‐70, were used to an engineer logic‐gated intracellular network CAR (LINK CAR) 66 …”

Section: Strategies For Controlling Car T‐cell Activitymentioning

confidence: 99%

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Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

Stock,

Klüver,

Fertig

et al. 2023

Intl Journal of Cancer

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The clinical application of chimeric antigen receptor (CAR) T‐cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood‐borne cancer types. However, CAR T‐cell therapy can lead to severe therapy‐associated toxicities including CAR‐related hematotoxicity, ON‐target OFF‐tumor toxicity, cytokine release syndrome (CRS) or immune effector cell‐associated neurotoxicity syndrome (ICANS). Just as CAR T‐cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T‐cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T‐cell activity. These approaches can mediate a reversible resting state or irreversible T‐cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T‐cells with T‐cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T‐cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T‐cell activity can be regulated intracellularly through a self‐regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T‐cells reversibly or irreversibly for preventing and for managing therapy‐associated toxicities.

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Delivery Systems Developed for Treatment Combinations to Improve Adoptive Cell Therapy

Xu,

Ni,

Gong

et al. 2024

Advanced Materials

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Adoptive cell therapy (ACT) has shown great success in the clinic for treating hematologic malignancies. However, solid tumor treatment with ACT monotherapy is still challenging, owing to insufficient expansion and rapid exhaustion of adoptive cells, tumor antigen downregulation/loss, and dense tumor extracellular matrix. Delivery strategies for combination cell therapy have great potential to overcome these hurdles. The delivery of vaccines, immune checkpoint inhibitors, cytokines, chemotherapeutics, and photothermal reagents in combination with adoptive cells, have been shown to improve the expansion/activation, decrease exhaustion, and promote the penetration of adoptive cells in solid tumors. Moreover, the delivery of nucleic acids to engineer immune cells directly in vivo holds promise to overcome many of the hurdles associated with the complex ex vivo cell engineering strategies. Here, these research advance, as well as the opportunities and challenges for integrating delivery technologies into cell therapy s are discussed, and the outlook for these emerging areas are criticlly analyzed.

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Co-opting signalling molecules enables logic-gated control of CAR T cells

Cited by 125 publications

References 65 publications

Harnessing the power of artificial intelligence to advance cell therapy

Harnessing the power of artificial intelligence to advance cell therapy

Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

Delivery Systems Developed for Treatment Combinations to Improve Adoptive Cell Therapy

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