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Article ; Online: Synthesizing a Smarter CAR T Cell: Advanced Engineering of T-cell Immunotherapies.

Zhu, Iowis / Piraner, Dan I / Roybal, Kole T

2023 Volume 11, Issue 8, Page(s) 1030–1043

Abstract: The immune system includes an array of specialized cells that keep us healthy by responding to pathogenic cues. Investigations into the mechanisms behind immune cell behavior have led to the development of powerful immunotherapies, including chimeric- ... ...

Abstract	The immune system includes an array of specialized cells that keep us healthy by responding to pathogenic cues. Investigations into the mechanisms behind immune cell behavior have led to the development of powerful immunotherapies, including chimeric-antigen receptor (CAR) T cells. Although CAR T cells have demonstrated efficacy in treating blood cancers, issues regarding their safety and potency have hindered the use of immunotherapies in a wider spectrum of diseases. Efforts to integrate developments in synthetic biology into immunotherapy have led to several advancements with the potential to expand the range of treatable diseases, fine-tune the desired immune response, and improve therapeutic cell potency. Here, we examine current synthetic biology advances that aim to improve on existing technologies and discuss the promise of the next generation of engineered immune cell therapies.
MeSH term(s)	Humans ; T-Lymphocytes ; Receptors, Antigen, T-Cell/genetics ; Immunotherapy, Adoptive ; Immunotherapy ; Neoplasms/therapy
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-07-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-22-0962
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Article ; Online: Toward the clinical development of synthetic immunity to cancer.

Garcia, Julie M / Burnett, Cassandra E / Roybal, Kole T

Immunological reviews

2023 Volume 320, Issue 1, Page(s) 83–99

Abstract: Synthetic 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, ... ...

Abstract	Synthetic 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.
MeSH term(s)	Humans ; Immunotherapy, Adoptive ; Neoplasms/therapy ; Receptors, Chimeric Antigen ; Immunotherapy ; Hematologic Neoplasms
Chemical Substances	Receptors, Chimeric Antigen
Language	English
Publishing date	2023-07-25
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13245
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Article ; Online: Refining cell therapy.

Roybal, Kole T

Science (New York, N.Y.)

2018 Volume 359, Issue 6380, Page(s) 1112–1113

MeSH term(s)	Animals ; Cell Engineering ; Cell- and Tissue-Based Therapy/methods ; Humans ; Neoplasms/therapy ; Receptors, Notch/chemistry ; Receptors, Notch/genetics ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/genetics ; T-Lymphocytes/transplantation
Chemical Substances	Receptors, Notch ; Recombinant Fusion Proteins
Language	English
Publishing date	2018-03-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aat0962
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Article ; Online: Toward the clinical development of synthetic immunity to cancer

Garcia, Julie M. / Burnett, Cassandra E. / Roybal, Kole T.

Immunological Reviews. 2023 Nov., v. 320, no. 1 p.83-99

2023

Abstract	Synthetic 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.
Keywords	antigens ; blood ; cancer therapy ; immunity ; immunotherapy ; probability ; synthetic biology
Language	English
Dates of publication	2023-11
Size	p. 83-99.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	REVIEW
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13245
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Article ; Online: Differential IL-12 signaling induces human natural killer cell activating receptor-mediated ligand-specific expansion.

Shemesh, Avishai / Pickering, Harry / Roybal, Kole T / Lanier, Lewis L

The Journal of experimental medicine

2022 Volume 219, Issue 8

Abstract: IL-12 is an essential cytokine involved in the generation of memory or memory-like NK cells. Mouse cytomegalovirus infection triggers NK receptor-induced, ligand-specific IL-12-dependent NK cell expansion, yet specific IL-12 stimulation ex vivo leading ... ...

Abstract	IL-12 is an essential cytokine involved in the generation of memory or memory-like NK cells. Mouse cytomegalovirus infection triggers NK receptor-induced, ligand-specific IL-12-dependent NK cell expansion, yet specific IL-12 stimulation ex vivo leading to NK cell proliferation and expansion is not established. Here, we show that IL-12 alone can sustain human primary NK cell survival without providing IL-2 or IL-15 but was insufficient to promote human NK cell proliferation. IL-12 signaling analysis revealed STAT5 phosphorylation and weak mTOR activation, which was enhanced by activating NK receptor upregulation and crosslinking leading to STAT5-dependent, rapamycin-sensitive, or TGFβ-sensitive NK cell IL-12-dependent expansion, independently of IL-12 receptor upregulation. Prolonged IL-2 culture did not impair IL-12-dependent ligand-specific NK cell expansion. These findings demonstrate that activating NK receptor stimulation promotes differential IL-12 signaling, leading to human NK cell expansion, and suggest adopting strategies to provide IL-12 signaling in vivo for ligand-specific IL-2-primed NK cell-based therapies.
MeSH term(s)	Cell Proliferation ; Humans ; Interleukin-12 ; Interleukin-2/pharmacology ; Ligands ; Receptors, Natural Killer Cell ; STAT5 Transcription Factor
Chemical Substances	Interleukin-2 ; Ligands ; Receptors, Natural Killer Cell ; STAT5 Transcription Factor ; Interleukin-12 (187348-17-0)
Language	English
Publishing date	2022-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20212434
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Article ; Online: Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities.

Roybal, Kole T / Lim, Wendell A

Annual review of immunology

2017 Volume 35, Page(s) 229–253

Abstract: The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells ... ...

Abstract	The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.
MeSH term(s)	Allergy and Immunology ; Animals ; Cancer Vaccines/immunology ; Genetic Engineering ; Humans ; Immunotherapy, Adoptive/methods ; Lymphocyte Activation ; Neoplasms/immunology ; Neoplasms/therapy ; Receptors, Antigen, T-Cell/genetics ; Recombinant Fusion Proteins/genetics ; Synthetic Biology ; T-Lymphocytes/immunology ; T-Lymphocytes/transplantation
Chemical Substances	Cancer Vaccines ; Receptors, Antigen, T-Cell ; Recombinant Fusion Proteins
Language	English
Publishing date	2017-04-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	604953-9
ISSN	1545-3278 ; 0732-0582
ISSN (online)	1545-3278
ISSN	0732-0582
DOI	10.1146/annurev-immunol-051116-052302
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Article ; Online: Naturally occurring T cell mutations enhance engineered T cell therapies.

Garcia, Julie / Daniels, Jay / Lee, Yujin / Zhu, Iowis / Cheng, Kathleen / Liu, Qing / Goodman, Daniel / Burnett, Cassandra / Law, Calvin / Thienpont, Chloë / Alavi, Josef / Azimi, Camillia / Montgomery, Garrett / Roybal, Kole T / Choi, Jaehyuk

Nature

2024 Volume 626, Issue 7999, Page(s) 626–634

Abstract: Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and ... ...

Abstract	Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function
MeSH term(s)	Humans ; CARD Signaling Adaptor Proteins/genetics ; CARD Signaling Adaptor Proteins/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Cytokines/biosynthesis ; Cytokines/immunology ; Cytokines/metabolism ; Evolution, Molecular ; Guanylate Cyclase/genetics ; Guanylate Cyclase/metabolism ; Immunotherapy, Adoptive/methods ; Lymphoma, T-Cell, Cutaneous/genetics ; Lymphoma, T-Cell, Cutaneous/immunology ; Lymphoma, T-Cell, Cutaneous/pathology ; Lymphoma, T-Cell, Cutaneous/therapy ; Mutation ; Phosphatidylinositol 3-Kinases ; Signal Transduction/genetics ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/transplantation
Chemical Substances	BCL10 protein, human ; CARD Signaling Adaptor Proteins ; CARD11 protein, human (EC 4.6.1.2) ; Cytokines ; Guanylate Cyclase (EC 4.6.1.2) ; MALT1 protein, human (EC 3.4.22.-) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; PIK3R3 protein, human (EC 2.7.1.137)
Language	English
Publishing date	2024-02-07
Publishing country	England
Document type	Journal Article
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-024-07018-7
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Article ; Online: Paving New Roads for CARs.

Hyrenius-Wittsten, Axel / Roybal, Kole T

Trends in cancer

2019 Volume 5, Issue 10, Page(s) 583–592

Abstract: Chimeric antigen receptor (CAR)-T cell therapy has had unprecedented impact in the treatment of hematological malignancies with few therapeutic options. However, it is clear that new strategies to enhance CAR-T cell function in solid tumors are needed to ...

Abstract	Chimeric antigen receptor (CAR)-T cell therapy has had unprecedented impact in the treatment of hematological malignancies with few therapeutic options. However, it is clear that new strategies to enhance CAR-T cell function in solid tumors are needed to make these living drugs widely applicable. The roadblock in solid tumors has led to a surge in the development of strategies to enhance CAR-T cells through advanced receptor design, new tumor sensing mechanisms, coexpression of genes that improve T cell function or stimulate tumor immunity, and precise genome editing. Here we provide an overview of the current state of the art in CAR-T cell engineering and a framework for the development of next-generation immune cell therapies with synthetic biology.
MeSH term(s)	Animals ; Genetic Engineering ; Hematologic Neoplasms/immunology ; Hematologic Neoplasms/therapy ; Humans ; Immunotherapy, Adoptive/methods ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/therapy ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Signal Transduction ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Tumor Microenvironment/immunology
Chemical Substances	Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen
Language	English
Publishing date	2019-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2019.09.005
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Article ; Online: Hyperstabilization of T cell microvilli contacts by chimeric antigen receptors.

Beppler, Casey / Eichorst, John / Marchuk, Kyle / Cai, En / Castellanos, Carlos A / Sriram, Venkataraman / Roybal, Kole T / Krummel, Matthew F

The Journal of cell biology

2022 Volume 222, Issue 3

Abstract: T cells typically recognize their ligands using a defined cell biology-the scanning of their membrane microvilli (MV) to palpate their environment-while that same membrane scaffolds T cell receptors (TCRs) that can signal upon ligand binding. Chimeric ... ...

Abstract	T cells typically recognize their ligands using a defined cell biology-the scanning of their membrane microvilli (MV) to palpate their environment-while that same membrane scaffolds T cell receptors (TCRs) that can signal upon ligand binding. Chimeric antigen receptors (CARs) present both a therapeutic promise and a tractable means to study the interplay between receptor affinity, MV dynamics and T cell function. CARs are often built using single-chain variable fragments (scFvs) with far greater affinity than that of natural TCRs. We used high-resolution lattice lightsheet (LLS) and total internal reflection fluorescence (TIRF) imaging to visualize MV scanning in the context of variations in CAR design. This demonstrated that conventional CARs hyper-stabilized microvillar contacts relative to TCRs. Reducing receptor affinity, antigen density, and/or multiplicity of receptor binding sites normalized microvillar dynamics and synapse resolution, and effector functions improved with reduced affinity and/or antigen density, highlighting the importance of understanding the underlying cell biology when designing receptors for optimal antigen engagement.
MeSH term(s)	Microvilli/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Single-Chain Antibodies/metabolism ; T-Lymphocytes ; Humans ; Antigens
Chemical Substances	Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen ; Single-Chain Antibodies ; Antigens
Language	English
Publishing date	2022-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.202205118
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Article: Modular design of synthetic receptors for programmed gene regulation in cell therapies

Zhu, Iowis / Liu, Raymond / Garcia, Julie M. / Hyrenius-Wittsten, Axel / Piraner, Dan I. / Alavi, Josef / Israni, Divya V. / Liu, Bin / Khalil, Ahmad S. / Roybal, Kole T.

Cell. 2022 Apr. 14, v. 185, no. 8

2022

Abstract: Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the ...

Abstract	Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors that we call synthetic intramembrane proteolysis receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the therapeutic potential of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation.
Keywords	genes ; humans ; proteolysis ; synthetic biology ; therapeutics ; transcription (genetics)
Language	English
Dates of publication	2022-0414
Size	p. 1431-1443.e16.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2022.03.023
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