Synapse-tuned CARs enhance immune cell anti-tumor activity

Chockley, Peter; Ibañez-Vega, Jorge; Krenciute, Giedre; Talbot, Lindsay J.

doi:10.1038/s41587-022-01650-2

Cited by 25 publications

(25 citation statements)

References 55 publications

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“…Specifically tailoring the immune synapse to achieve a desired functional outcome has recently been applied to amplify anti-tumor responses of CAR NK cells 40 . In this setting, introduction of a scaffolding domain augmented synapse formation between CAR NK cells and tumor cells, resulting in notably improved tumor control by fine-tuning adhesion properties 40 .…”

Section: Discussionmentioning

confidence: 99%

Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells

Hammer,

Perica,

van Ooijen

et al. 2023

Preprint

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SUMMARYAllogeneic cell therapies hold promise for broad clinical implementation, but face limitations due to potential rejection by the recipient immune system. Silencing of beta-2-microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection, although absence ofB2Mtriggers missing-self responses by recipient natural killer (NK) cells. Here, we demonstrate that deletion of the adhesion ligandsCD54andCD58on targets cells robustly dampens NK cell reactivity across all sub-populations. Genetic deletion ofCD54andCD58inB2M-deficient allogeneic chimeric antigen receptor (CAR) T and multi-edited induced pluripotent stem cell (iPSC)-derived NK cells reduces their susceptibility to rejection by NK cellsin vitroandin vivowithout affecting their anti-tumor effector potential. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection of allogeneic immune cells for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells

Hammer,

Perica,

van Ooijen

et al. 2023

Preprint

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“…Recently, innovative synapse-tuned CAR NK cells have been devised by incorporating a PDZ binding motif (PDZbm), important for cell polarization and synapse formation, within the CAR construct (Figure 2B). 124 This modification enhanced the strength of the synapse and the polarization of CAR T and CAR NK cells, resulting in improved effector cell function both in vitro and in vivo. 124 Other emerging approaches to broaden the scope of antigen binding include the use of vaccines to promote antigen display on h CD19, CD20, CD22, CD70, CD13, CD79b, GD2, and/or PSMA.…”

Section: Exploration Of Novel Targeting Approachesmentioning

confidence: 99%

“…124 This modification enhanced the strength of the synapse and the polarization of CAR T and CAR NK cells, resulting in improved effector cell function both in vitro and in vivo. 124 Other emerging approaches to broaden the scope of antigen binding include the use of vaccines to promote antigen display on h CD19, CD20, CD22, CD70, CD13, CD79b, GD2, and/or PSMA.…”

Section: Exploration Of Novel Targeting Approachesmentioning

confidence: 99%

Next‐generation chimeric antigen receptors for T‐ and natural killer‐cell therapies against cancer

Li,

Rezvani,

Rafei

2023

Immunological Reviews

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SummaryAdoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor‐specific antigens that can be targeted without cross‐reactivity against normal tissues. This may lead to unwanted on‐target off‐tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, thus mitigating on‐target off‐tumor adverse effects. In this review, we outline the current strategies being explored to improve CAR selectivity toward tumor cells with a focus on natural killer (NK) cells, and the progress made in translating these strategies to the clinic.

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“…46 Beyond the ECD, others have included post-synaptic density-95, discs large and zona occuldens 1 binding moieties (PDZbm) domains in CAR intracellular domains-organizing the CAR synapse to mimic the TCR synapse more closely-and have demonstrated that these designs result in greater signaling outputs. 47 In a recent preprint, Finn et al 48 sought to mimic the "horizontal" signaling of TCR complexes and developed valency-controlled receptors, using small molecules to increase the clustering of CARs. New receptor designs have sought to employ other natural multichain immunoreceptors, hypothesizing that multichain receptors would allow for greater signaling diversity, and improved signaling.…”

Section: Using Natural Receptor Signaling To Educate Synthetic Designmentioning

confidence: 99%

“…Similarly, some groups have fused heavy and light scFv chains to the constant regions of a TCR alpha and beta chain, creating HLA independent T‐cell receptors known as “HIT” receptors 46 . Beyond the ECD, others have included post‐synaptic density‐95, discs large and zona occuldens 1 binding moieties (PDZbm) domains in CAR intracellular domains—organizing the CAR synapse to mimic the TCR synapse more closely—and have demonstrated that these designs result in greater signaling outputs 47 . In a recent preprint, Finn et al 48 sought to mimic the “horizontal” signaling of TCR complexes and developed valency‐controlled receptors, using small molecules to increase the clustering of CARs.…”

Section: Principle 1: Rooting Synthetic Immunology In Current Underst...mentioning

confidence: 99%

Toward the clinical development of synthetic immunity to cancer

Garcia

Burnett

Roybal

2023

Immunological Reviews

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SummarySynthetic biology (synbio) tools, such as chimeric antigen receptors (CARs), have been designed to target, activate, and improve immune cell responses to tumors. These therapies have demonstrated an ability to cure patients with blood cancers. However, there are significant challenges to designing, testing, and efficiently translating these complex cell therapies for patients who do not respond or have immune refractory solid tumors. The rapid progress of synbio tools for cell therapy, particularly for cancer immunotherapy, is encouraging but our development process should be tailored to increase translational success. Particularly, next‐generation cell therapies should be rooted in basic immunology, tested in more predictive preclinical models, engineered for potency with the right balance of safety, educated by clinical findings, and multi‐faceted to combat a range of suppressive mechanisms. Here, we lay out five principles for engineering future cell therapies to increase the probability of clinical impact, and in the context of these principles, we provide an overview of the current state of synbio cell therapy design for cancer. Although these principles are anchored in engineering immune cells for cancer therapy, we posit that they can help guide translational synbio research for broad impact in other disease indications with high unmet need.

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Synapse-tuned CARs enhance immune cell anti-tumor activity

Cited by 25 publications

References 55 publications

Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells

Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells

Next‐generation chimeric antigen receptors for T‐ and natural killer‐cell therapies against cancer

Toward the clinical development of synthetic immunity to cancer

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