Engineering advanced logic and distributed computing in human CAR immune cells

Cho, Jang Hwan; Okuma, Atsushi; Sofjan, Katri; Lee, Seung‐Hee; Collins, James J.; Wong, Wilson

doi:10.1038/s41467-021-21078-7

Cited by 94 publications

(71 citation statements)

References 48 publications

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“…The system seems able to improve the specificity and controllability [ 91 ] of the immune cell engineering strategy. Thus, the SUPRA CAR system has the potential to reduce CRS without reducing the antitumor response [ 92 ].…”

Section: Future Prospectmentioning

confidence: 99%

Cytokine Release Syndrome Associated with T-Cell-Based Therapies for Hematological Malignancies: Pathophysiology, Clinical Presentation, and Treatment

Cosenza

Sacchi

Pozzi

2021

IJMS

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Cytokines are a broad group of small regulatory proteins with many biological functions involved in regulating the hematopoietic and immune systems. However, in pathological conditions, hyperactivation of the cytokine network constitutes the fundamental event in cytokine release syndrome (CRS). During the last few decades, the development of therapeutic monoclonal antibodies and T-cell therapies has rapidly evolved, and CRS can be a serious adverse event related to these treatments. CRS is a set of toxic adverse events that can be observed during infection or following the administration of antibodies for therapeutic purposes and, more recently, during T-cell-engaging therapies. CRS is triggered by on-target effects induced by binding of chimeric antigen receptor (CAR) T cells or bispecific antibody to its antigen and by subsequent activation of bystander immune and non-immune cells. CRS is associated with high circulating concentrations of several pro-inflammatory cytokines, including interleukins, interferons, tumor necrosis factors, colony-stimulating factors, and transforming growth factors. Recently, considerable developments have been achieved with regard to preventing and controlling CRS, but it remains an unmet clinical need. This review comprehensively summarizes the pathophysiology, clinical presentation, and treatment of CRS caused by T-cell-engaging therapies utilized in the treatment of hematological malignancies.

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Section: Future Prospectmentioning

confidence: 99%

Cytokine Release Syndrome Associated with T-Cell-Based Therapies for Hematological Malignancies: Pathophysiology, Clinical Presentation, and Treatment

Cosenza

Sacchi

Pozzi

2021

IJMS

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“…Many of the pitfalls of CAR T cells are being addressed with complementary solutions such as additional gene editing to enhance the T cell immune response or the co-administration of immunomodulating compounds [4][5][6][7][8].…”

Section: Discussionmentioning

confidence: 99%

“…can potentially sensitize tumors to cell-mediated cytotoxicity [5]. Furthermore, synthetic biology approaches that incorporate controllable domains [6][7][8] are being utilized to design CARs responsive to drugs or antigenic cues in order to tune the strength, duration and specificity of the inflammatory response. While promising, all of these strategies require additional drug compounds or genetic modifications, introducing further complexity in a therapeutic regimen that is already laborious and sensitive.…”

Section: Introductionmentioning

confidence: 99%

speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing

Roberto

Castellanos-Rueda

Schlatter

et al. 2021

Preprint

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Chimeric antigen receptors (CARs) consist of an extracellular antigen-binding region fused to intracellular signaling domains, thus enabling customized T cell responses against target cells. Due to the low-throughput process of systematically designing and functionally testing CARs, only a small set of immune signaling domains have been thoroughly explored, despite their major role in T cell activation, effector function and persistence. Here, we present speedingCARs, an integrated method for engineering CAR T cells by signaling domain shuffling and functional screening by single-cell sequencing. Leveraging the inherent modularity of natural signaling domains, we generated a diverse library of 180 unique CAR variants, which were genomically integrated into primary human T cells by CRISPR-Cas9. Functional and pooled screening of the CAR T cell library was performed by co-culture with tumor cells, followed by single-cell RNA sequencing (scRNA-seq) and single-cell CAR sequencing (scCAR-seq), thus enabling high-throughput profiling of multi-dimensional cellular responses. This led to the discovery of several CAR variants that retained the ability to kill tumor cells, while also displaying diverse transcriptional signatures and T cell phenotypes. In summary, speedingCARs substantially expands and characterizes the signaling domain combinations suited for CAR design and supports the engineering of next-generation T cell therapies.

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“…This platform is thus an easily controllable and combinatorial system that better targets tumour cells co-expressing antigens rather than healthy surrounding tissue. Aside from AND gates, other logic gates, such as OR and NOT gates, have been engineered to recognize different combinations of surface antigens to increase tumour targeting over the targeting of healthy cells 105 , 118 , 123 .…”

Section: Mammalian Therapeuticsmentioning

confidence: 99%

Theranostic cells: emerging clinical applications of synthetic biology

McNerney

Doiron

et al. 2021

Nat Rev Genet

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Synthetic biology seeks to redesign biological systems to perform novel functions in a predictable manner. Recent advances in bacterial and mammalian cell engineering include the development of cells that function in biological samples or within the body as minimally invasive diagnostics or theranostics for the real-time regulation of complex diseased states. Ex vivo and in vivo cell-based biosensors and therapeutics have been developed to target a wide range of diseases including cancer, microbiome dysbiosis and autoimmune and metabolic diseases. While probiotic therapies have advanced to clinical trials, chimeric antigen receptor (CAR) T cell therapies have received regulatory approval, exemplifying the clinical potential of cellular therapies. This Review discusses preclinical and clinical applications of bacterial and mammalian sensing and drug delivery platforms as well as the underlying biological designs that could enable new classes of cell diagnostics and therapeutics. Additionally, we describe challenges that must be overcome for more rapid and safer clinical use of engineered systems.

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Engineering advanced logic and distributed computing in human CAR immune cells

Cited by 94 publications

References 48 publications

Cytokine Release Syndrome Associated with T-Cell-Based Therapies for Hematological Malignancies: Pathophysiology, Clinical Presentation, and Treatment

Cytokine Release Syndrome Associated with T-Cell-Based Therapies for Hematological Malignancies: Pathophysiology, Clinical Presentation, and Treatment

speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing

Theranostic cells: emerging clinical applications of synthetic biology

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