Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization

Leung, Wai Hang; Martin, Unja; Garrett, Tracy E.; Horton, Holly M.; Certo, Michael; Blazar, Bruce R.; Morgan, Richard A.; Gregory, Philip D.; Jarjour, Jordan; Astrakhan, Alexander

doi:10.1172/jci.insight.124430

Cited by 61 publications

(84 citation statements)

References 55 publications

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“…Irrespective of mechanism, these results demonstrate that cessation of CAR signaling is a potent maneuver that results in augmented function in cell populations that are transitioning to exhaustion or in those already imprinted with hallmark features of exhaustion, and is distinct from that which can be achieved with PD-1/PD-L1 blockade. Advances in synthetic biology have enabled the development of several tunable CAR platforms which have been optimized to mitigate CAR-mediated toxicity (Bejestani et al, 2017;Cho et al, 2018;Leung et al, 2019;Rodgers et al, 2016;Wu et al, 2015). Our data suggest that such platforms, including the DD-CAR system described here, may enhance CAR-T cell potency as a result of temporal control of CAR-T cell signaling.…”

Section: Discussionmentioning

confidence: 70%

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

Weber

Lynn

Parker

et al. 2020

Preprint

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T cell exhaustion limits immune responses against cancer and is a major cause of resistance to CAR-T cell therapeutics. Using a model wherein tonic CAR signaling induces hallmark features of exhaustion, we employed a drug-regulatable CAR to test the impact of transient cessation of receptor signaling (i.e. "rest") on the development and maintenance of exhaustion. Induction of rest in exhausting or already-exhausted CAR-T cells resulted in acquisition of a memory-like phenotype, improved antitumor functionality, and wholescale transcriptional and epigenetic reprogramming. Similar results were achieved with the Src kinase inhibitor dasatinib, which reversibly suppresses CAR signaling. The degree of functional reinvigoration was proportional to the duration of rest and was associated with expression of transcription factors TCF1 and LEF1. This work demonstrates that transient cessation of CAR-T cell signaling can enhance anti-tumor potency by preventing or reversing exhaustion and challenges the paradigm that exhaustion is an epigenetically fixed state.

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Section: Discussionmentioning

confidence: 70%

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

Weber

Lynn

Parker

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…To address the lack of control and tumor specificity associated with CAR-T cells, several promising strategies have been developed including CARs for combinatorial antigen recognition [8][9][10][11][12][13][14] , affinity-tuned CARs to minimize killing of healthy cells expressing low levels of target antigen [15][16][17][18][19][20] and CARs whose function can be regulated by administration of small molecules or soluble proteins 10,[21][22][23][24][25][26][27][28][29] . Despite these important advances, there is still a need for improvement.…”

mentioning

confidence: 99%

Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function

et al. 2020

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T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CART cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ONswitch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.

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“…However, due to its immunosuppressive activity, rapamycin is considered to be suboptimal. A very recent preclinical CAR study showed promising results with lower concentrations of this drug ( 39 ). Nevertheless, if available, a safe compound without any immunocompromising effect—like A1120—would be preferred, especially for immunotherapeutic applications.…”

Section: Discussionmentioning

confidence: 99%

A conformation-specific ON-switch for controlling CAR T cells with an orally available drug

Zajc

Dobersberger

Schaffner

et al. 2020

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

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Molecular ON-switches in which a chemical compound induces protein–protein interactions can allow cellular function to be controlled with small molecules. ON-switches based on clinically applicable compounds and human proteins would greatly facilitate their therapeutic use. Here, we developed an ON-switch system in which the human retinol binding protein 4 (hRBP4) of the lipocalin family interacts with engineered hRBP4 binders in a small molecule-dependent manner. Two different protein scaffolds were engineered to bind to hRBP4 when loaded with the orally available small molecule A1120. The crystal structure of an assembled ON-switch shows that the engineered binder specifically recognizes the conformational changes induced by A1120 in two loop regions of hRBP4. We demonstrate that this conformation-specific ON-switch is highly dependent on the presence of A1120, as demonstrated by an ∼500-fold increase in affinity upon addition of the small molecule drug. Furthermore, the ON-switch successfully regulated the activity of primary human CAR T cells in vitro. We anticipate that lipocalin-based ON-switches have the potential to be broadly applied for the safe pharmacological control of cellular therapeutics.

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Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization

Cited by 61 publications

References 55 publications

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function

A conformation-specific ON-switch for controlling CAR T cells with an orally available drug

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