Engineering clinically-approved drug gated CAR circuits

H, Li; Wong, Nichol M.L.; Tague, Elliot P.; Jt, Ngo; As, Khalil; Wong, William W.

doi:10.1101/2020.12.14.419812

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…These studies collectively illustrate that the modular CAR template can customize how macrophages respond to target antigens. Future efforts to engineer CAR-M will likely tap into the plethora of sophisticated CAR designs that have been developed for T cells, incorporating tandem activation domains ( 71 ), multi-antigen logic gates ( 72 , 73 ), or drug-sensitive modules ( 74 – 76 ).…”

Section: Car-m: Macrophages Take the Wheelmentioning

confidence: 99%

Engineered CAR-Macrophages as Adoptive Immunotherapies for Solid Tumors

2021

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Cellular immunotherapies represent a promising approach for the treatment of cancer. Engineered adoptive cell therapies redirect and augment a leukocyte’s inherent ability to mount an immune response by introducing novel anti-tumor capabilities and targeting moieties. A prominent example of this approach is the use of T cells engineered to express chimeric antigen receptors (CARs), which have demonstrated significant efficacy against some hematologic malignancies. Despite increasingly sophisticated strategies to harness immune cell function, efficacy against solid tumors has remained elusive for adoptive cell therapies. Amongst cell types used in immunotherapies, however, macrophages have recently emerged as prominent candidates for the treatment of solid tumors. In this review, we discuss the use of monocytes and macrophages as adoptive cell therapies. Macrophages are innate immune cells that are intrinsically equipped with broad therapeutic effector functions, including active trafficking to tumor sites, direct tumor phagocytosis, activation of the tumor microenvironment and professional antigen presentation. We focus on engineering strategies for manipulating macrophages, with a specific focus on CAR macrophages (CAR-M). We highlight CAR design for macrophages, the production of CAR-M for adoptive cell transfer, and clinical considerations for their use in treating solid malignancies. We then outline recent progress and results in applying CAR-M as immunotherapies. The recent development of engineered macrophage-based therapies holds promise as a key weapon in the immune cell therapy armamentarium.

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Section: Car-m: Macrophages Take the Wheelmentioning

confidence: 99%

Engineered CAR-Macrophages as Adoptive Immunotherapies for Solid Tumors

2021

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“…Li a Wong odhalili pozitivní korelaci mezi nevírou ve svobodnou vůli a depresivními symptomy. 66 Jejich zjištění je v souladu jak s poznámkami o pocitech bezmocnosti zmíněnými výše, tak s dlouholetým výzkumem Twengea a kolektivu. 67 Ti na metaanalýze dat z druhé poloviny 20. století ukázali pozitivní korelaci mezi jedincovým pocitem kontroly nad jeho životem a jeho psychickým zdravím.…”

Section: Problém Strategie První Osoby V Diskuzi O Svobodné Vůliunclassified

Problém s obhajobou svobodné vůle za pomoci dat první osoby

Kish

2022

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Text obhajuje názor, že tzv. argumenty první osoby pro svobodnou vůli nesplňují vysoký epistemický standard, a proto není vhodné jimi dokazovat existenci svobody vůle. V první části je krátce uvedena problematika svobodné vůle a charakterizace skupiny důkazů, které její existenci obhajují odkazem na lidské prožívání svobodného rozhodování. V druhé části argumentu je vylíčeno, jak se idea svobodné vůle projevuje na každodenním lidském fungování a jaký má dopad na lidský blahobyt. Třetí část textu obhajuje tvrzení, že kvůli spojení svobodné vůle s každodenní lidskou praxí je nezbytné, aby měly argumenty ve prospěch či neprospěch svobody vůle vysokou míru plauzibility a robustnosti. Čtvrtá část dokazuje, že argumenty první osoby pro svobodnou vůli na vysoký standard jistoty nedosahují, protože metody nabytí dat první osoby jsou přinejmenším pochybné a data sama vysoce proměnlivá. V páté a poslední části je předložen závěr, dle kterého je jakákoliv kredibilita argumentů první osoby pro svobodu vůle kvůli jejich principiální nerobustnosti apriori signifikantně snížena.

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“…Complementary strategies using a function-on approach include several inducible devices with tunable CAR T cell function control: small molecule-inducible CAR devices ( 23 – 27 ), intermediary antibody or protein-based CAR devices ( 28 – 30 ), as well as light/ultrasound-responsive noninvasive devices ( 31 – 33 ). Synthetic Notch (synNotch) receptor-based circuits were also designed to enhance the precision of tumor recognition ( 34 – 38 ).…”

mentioning

confidence: 99%

Engineering genetic devices for in vivo control of therapeutic T cell activity triggered by the dietary molecule resveratrol

Yang

Yin

et al. 2021

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

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Chimeric antigen receptor (CAR)–engineered T cell therapies have been recognized as powerful strategies in cancer immunotherapy; however, the clinical application of CAR-T is currently constrained by severe adverse effects in patients, caused by excessive cytotoxic activity and poor T cell control. Herein, we harnessed a dietary molecule resveratrol (RES)–responsive transactivator and a transrepressor to develop a repressible transgene expression (RESrep) device and an inducible transgene expression (RESind) device, respectively. After optimization, these tools enabled the control of CAR expression and CAR-mediated antitumor function in engineered human cells. We demonstrated that a resveratrol-repressible CAR expression (RESrep-CAR) device can effectively inhibit T cell activation upon resveratrol administration in primary T cells and a xenograft tumor mouse model. Additionally, we exhibit how a resveratrol-inducible CAR expression (RESind-CAR) device can achieve fine-tuned and reversible control over T cell activation via a resveratrol-titratable mechanism. Furthermore, our results revealed that the presence of RES can activate RESind-CAR T cells with strong anticancer cytotoxicity against cells in vitro and in vivo. Our study demonstrates the utility of RESrep and RESind devices as effective tools for transgene expression and illustrates the potential of RESrep-CAR and RESind-CAR devices to enhance patient safety in precision cancer immunotherapies.

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Engineering clinically-approved drug gated CAR circuits

Cited by 4 publications

References 46 publications

Engineered CAR-Macrophages as Adoptive Immunotherapies for Solid Tumors

Engineered CAR-Macrophages as Adoptive Immunotherapies for Solid Tumors

Problém s obhajobou svobodné vůle za pomoci dat první osoby

Engineering genetic devices for in vivo control of therapeutic T cell activity triggered by the dietary molecule resveratrol

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