Masked Chimeric Antigen Receptor for Tumor-Specific Activation

Han, Xuemei; Bryson, Paul D.; Zhao, Yifan; Cinay, Gunce E.; Li, Si; Guo, Yunfei; Siriwon, Natnaree; Wang, Pin

doi:10.1016/j.ymthe.2016.10.011

Cited by 86 publications

(77 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, a masked CAR consists of a masking peptide that blocks the antigen-binding site and a protease-sensitive linker [75] . Proteases that are commonly active in the tumor microenvironment can cleave the linker and disengage the masking peptide, thereby enabling CARs to be functional at the local tumor sites.…”

Section: Improvements In Safetymentioning

confidence: 99%

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

2017

View full text Add to dashboard Cite

Natural killer (NK) cells are potential effector cells in cell-based cancer immunotherapy, particularly in the control of hematological malignancies. The chimeric antigen receptor (CAR) is an artificially modified fusion protein that consists of an extracellular antigen recognition domain fused to an intracellular signaling domain. T cells genetically modified with a CAR have demonstrated remarkable success in the treatment of hematological cancers. Compared to T cells, CAR-transduced NK cells (CAR-NK) exhibit several advantages, such as safety in clinical use, the mechanisms by which they recognize cancer cells, and their abundance in clinical samples. Human primary NK cells and the NK-92 cell line have been successfully transduced to express CARs against both hematological cancers and solid tumors in pre-clinical and clinical trials. However, many challenges and obstacles remain, such as the ex vivo expansion of CAR-modified primary NK cells and the low transduction efficiency of NK cells. Many strategies and technologies have been developed to improve the safety and therapeutic efficacy in CAR-based immunotherapy. Moreover, NK cells express a variety of activating receptors (NKRs), such as CD16, NKG2D, CD226 and NKp30, which might specifically recognize the ligands expressed on tumor cells. Based on the principle of NKR recognition, a strategy that targets NKRs is rapidly emerging. Given the promising clinical progress described in this review, CAR- and NKR-NK cell-based immunotherapy are likely promising new strategies for cancer therapy.

show abstract

Section: Improvements In Safetymentioning

confidence: 99%

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

2017

View full text Add to dashboard Cite

show abstract

“…Induction of CAR function was also exemplified in the case of a HIF-CAR which was design to incorporate HIF1α domain making it sensitive to oxygen and degraded under normoxia conditions [299]. Also, receptor potentiation by proteolysis of a small masking tag degraded in the presence of specific proteases expressed in the tumor microenvironment was elegantly demonstrated for an EGFR-specific CAR [300]. Recently, Helsen et al reported the use of a T-cell antigen coupler (TAC) chimeric receptor [301] which consists of a double targeting moiety: an antigen-specific scFv followed by a CD3-activating scFv built on a CD4 scaffold.…”

Section: Control Of Transgene Expression and T-cell Functionmentioning

confidence: 99%

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Eisenberg

Hoogi

Shamul

et al. 2019

Advanced Drug Delivery Reviews

View full text Add to dashboard Cite

“…5). Masked CARs achieve this by including an inhibitory peptide, tethered extracellularly via a cleavable linker, that reversibly blocks the scFv and keeps the T cells in an off state until they reach the tumour microenvironment 93 . Once there, proteases specifically secreted locally cleave the inhibitory peptide and unmask the CAR, priming it for targeting tumour cells.…”

Section: Nature Biomedical Engineeringmentioning

confidence: 99%

“…Chimeric cytokine receptors -engineered chemokine receptors with modified functions -can be used to achieve selective expansion of T cells by an administered cytokine 126 Once the T cell reaches the tumour microenvironment (TME), specific proteases liberate the decoy peptide and unmask the CAR for targeting 93 . b, Oxygen-sensing CARs are selectively degraded under normoxia, yet stably expressed in hypoxic conditions.…”

Section: Homing and Traffickingmentioning

confidence: 99%

Programming CAR-T cells to kill cancer

2018

View full text Add to dashboard Cite

T cells engineered to express chimeric antigen receptors (CARs) that are specific for tumour antigens have led to high complete response rates in patients with haematologic malignancies. Despite this early success, major challenges to the broad application of CAR-T cells as cancer therapies remain, including treatment-associated toxicities and cancer relapse with antigen-negative tumours. Targeting solid tumours with CAR-T cells poses additional obstacles because of the paucity of tumourspecific antigens and the immunosuppressive effects of the tumour microenvironment. To overcome these challenges, T cells can be programmed with genetic modules that increase their therapeutic potency and specificity. In this Review Article, we survey major advances in the engineering of next-generation CAR-T therapies for haematologic cancers and solid cancers, with particular emphasis on strategies for the control of CAR specificity and activity and on approaches for improving CAR-T-cell persistence and overcoming immunosuppression. We also lay out a roadmap for the development of off-the-shelf CAR-T cells.

show abstract

Masked Chimeric Antigen Receptor for Tumor-Specific Activation

Cited by 86 publications

References 51 publications

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Programming CAR-T cells to kill cancer

Contact Info

Product

Resources

About