Cell-Based Therapeutics: The Next Pillar of Medicine

Fischbach, Michael A.; Bluestone, Jeffrey A.; Lim, Wendell A.

doi:10.1126/scitranslmed.3005568

Cited by 363 publications

(305 citation statements)

References 27 publications

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“…In addition to direct administration to patients, inhibitors can be used during in vitro expansion of cells for adoptive cell transfer therapies to improve the functional stability of T cells after transfer into patients 179 . With the advent of chimeric antigen receptor (CAR) technologies to redirect cytotoxic T cells to specific antigenic targets comes the potential to engineer CARs that are linked to different intracellular signalling domains that promote distinct functions in CD4 + T cells 180,181 .…”

Section: Bet Inhibitorsmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Section: Bet Inhibitorsmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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“…T lymphocytes are highly motile cells of the adaptive immune system that play critical roles in cell-mediated immunity. Their use is currently being heavily explored in cell-based therapeutic applications in human clinical trials and in preclinical models, especially in cancer and autoimmunity (1,2,26,27). We therefore tested whether the homing of engineered T lymphocytes could be redirected to the orthogonal CNO signal in a mouse.…”

Section: Identification Of Orthogonal Gpcr That Controls Hl-60 Neutromentioning

confidence: 99%

Synthetic control of mammalian-cell motility by engineering chemotaxis to an orthogonal bioinert chemical signal

Park

Rhau

Hermann

et al. 2014

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

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103

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Directed migration of diverse cell types plays a critical role in biological processes ranging from development and morphogenesis to immune response, wound healing, and regeneration. However, techniques to direct, manipulate, and study cell migration in vitro and in vivo in a specific and facile manner are currently limited. We conceived of a strategy to achieve direct control over cell migration to arbitrary user-defined locations, independent of native chemotaxis receptors. Here, we show that genetic modification of cells with an engineered G protein-coupled receptor allows us to redirect their migration to a bioinert drug-like small molecule, clozapine-Noxide (CNO). The engineered receptor and small-molecule ligand form an orthogonal pair: The receptor does not respond to native ligands, and the inert drug does not bind to native cells. CNOresponsive migration can be engineered into a variety of cell types, including neutrophils, T lymphocytes, keratinocytes, and endothelial cells. The engineered cells migrate up a gradient of the drug CNO and transmigrate through endothelial monolayers. Finally, we demonstrate that T lymphocytes modified with the engineered receptor can specifically migrate in vivo to CNO-releasing beads implanted in a live mouse. This technology provides a generalizable genetic tool to systematically perturb and control cell migration both in vitro and in vivo. In the future, this type of migration control could be a valuable module for engineering therapeutic cellular devices.GPCR | cellular therapeutics | synthetic biology

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“…However, we have now entered the era of the third pillar of medicine: cell therapy (8). "Cells uniquely sense their surroundings, make decisions and exhibit varied and regulable behaviors," such as targeting (8).…”

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confidence: 99%

PDGFB-based stem cell gene therapy increases bone strength in the mouse

Chen

Baylink

Brier-Jones

et al. 2015

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

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Substantial advances have been made in the past two decades in the management of osteoporosis. However, none of the current medications can eliminate the risk of fracture and rejuvenate the skeleton. To this end, we recently reported that transplantation of hematopoietic stem/progenitor cells (HSCs) or Sca1 + cells engineered to overexpress FGF2 results in a significant increase in lamellar bone matrix formation at the endosteum; but this increase was attended by the development of secondary hyperparathyroidism and severe osteomalacia. Here we switch the therapeutic gene to PDGFB, another potent mitogen for mesenchymal stem cells (MSCs) but potentially safer than FGF2. We found that modest overexpression of PDGFB using a relatively weak phosphoglycerate kinase (PGK) promoter completely avoided osteomalacia and secondary hyperparathyroidism, and simultaneously increased trabecular bone formation and trabecular connectivity, and decreased cortical porosity. These effects led to a 45% increase in the bone strength. Transplantation of PGK-PDGFB-transduced Sca1 + cells increased MSC proliferation, raising the possibility that PDGF-BB enhances expansion of MSC in the vicinity of the hematopoietic niche where the osteogenic milieu propels the differentiation of MSCs toward an osteogenic destination. Our therapy should have potential clinical applications for patients undergoing HSC transplantation, who are at high risk for osteoporosis and bone fractures after total body irradiation preconditioning. It could eventually have wider application once the therapy can be applied without the preconditioning.PDGFB | hematopoietic stem cells | bone formation | gene therapy

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Cell-Based Therapeutics: The Next Pillar of Medicine

Cited by 363 publications

References 27 publications

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Synthetic control of mammalian-cell motility by engineering chemotaxis to an orthogonal bioinert chemical signal

PDGFB-based stem cell gene therapy increases bone strength in the mouse

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