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Link to original content: http://pubmed.ncbi.nlm.nih.gov/38491394/
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Review
. 2024 Mar 15;44(1):15.
doi: 10.1186/s41232-024-00327-4.

Designer cell therapy for tissue regeneration

Noyuri Zama  1   2 , Satoshi Toda  3
Affiliations
Review

Designer cell therapy for tissue regeneration

Noyuri Zama et al. Inflamm Regen. .

Abstract

Cancer cell therapy, particularly chimeric antigen receptor (CAR) T-cell therapy for blood cancers, has emerged as a powerful new modality for cancer treatment. Therapeutic cells differ significantly from conventional drugs, such as small molecules and biologics, as they possess cellular information processing abilities to recognize and respond to abnormalities in the body. This capability enables the targeted delivery of therapeutic factors to specific locations and times. Various types of designer cells have been developed and tested to overcome the shortcomings of CAR T cells and expand their functions in the treatment of solid tumors. In particular, synthetic receptor technologies are a key to designing therapeutic cells that specifically improve tumor microenvironment. Such technologies demonstrate great potential for medical applications to regenerate damaged tissues as well that are difficult to cure with conventional drugs. In this review, we introduce recent developments in next-generation therapeutic cells for cancer treatment and discuss the application of designer therapeutic cells for tissue regeneration.

Keywords: Cell engineering; Cell therapy; Synthetic receptor; Tissue microenvironment; Tissue regeneration.

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Conflict of interest statement

S.T. is an inventor on a patent for synthetic Notch receptors (Patent No.: US 10,590,182 B2) held by the Regents of the University of California, which is licensed to Gilead. N.Z. declares no competing interests.

Figures

Fig. 1
Fig. 1
Concept of designer therapeutic cells. A Designer therapeutic cells. Cells express receptors that sense environmental molecules. These receptors activate intracellular signaling networks to produce various cellular responses. Such cell systems can be engineered to develop designer therapeutic cells that are programmed to sense disease-related factors and process intracellular signals to output specific therapeutic actions. B Advantages of designer therapeutic cells over molecular drugs. While molecular drugs passively diffuse into the body, designer therapeutic cells can sense and reach the disease site, control behaviors such as proliferation and differentiation, and produce user-defined therapeutic factors. These properties enable the specificity and autonomy of therapeutic effects by designer cells (adopted from Lim [1], with modifications)
Fig. 2
Fig. 2
Programming sensing and responsiveness in designer therapeutic cells through synthetic Notch receptors. Notch is a natural signal transduction receptor that recognizes the Delta ligand. The Notch–Delta interaction induces the cleavage of Notch, leading to the release of the Notch intracellular domain. Subsequently, this intracellular domain translocates into the nucleus, where it regulates the expression of Notch target genes. In contrast, the synNotch system contains an extracellular antibody/nanobody domain that recognizes user-defined antigens. SynNotch is also cleaved by antigen recognition; however, it can induce the expression of user-defined target genes by releasing artificial transcription factors
Fig. 3
Fig. 3
Next-generation CAR T cells with synNotch circuit for targeting immune-suppressive solid tumors. The immunosuppressive (cold) tumor microenvironment around solid tumors blocks CAR T-cell functions. SynNotch circuit–engineered CAR T cells, designed to detect tumor antigens and induce IL-2, can be locally activated with autocrine IL-2 signaling at solid tumor sites. This local activation forms immuno-active (hot) microenvironment to facilitate increased infiltration into solid tumors, which allows successful elimination of solid tumors in a mouse model
Fig. 4
Fig. 4
Designer therapeutic cells for tissue regeneration. Designer therapeutic cells are engineered using synNotch to recognize abnormal cells or damage markers specific to damaged tissues. Designer cells then produce a combination of therapeutic factors, including growth factors, cytokines, and biologics, which have different functions to support tissue regeneration by removing damage-related abnormal factors and inducing the proliferation and differentiation of stem cells. Using designer therapeutic cells, potent therapeutic factors can be delivered specifically to damaged tissues with less toxicity to healthy tissues
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