Engineering Axl specific CAR and SynNotch receptor for cancer therapy

Cho, Jang Hwan; Okuma, Atsushi; Al-Rubaye, Dalal; Intisar, Ejaj; Junghans, Richard P.; Wong, Wilson

doi:10.1038/s41598-018-22252-6

Cited by 47 publications

(39 citation statements)

References 28 publications

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“…Two other selected anti-AXL mAbs, D9 and E8, are efficient in inhibiting the proliferation and migration of pancreatic cancer cells through blocking the phosphorylation of AXL and downstream molecules without affecting GAS6 binding [249]. Other anti-AXL mAbs include 20G7-D9 [84], MAb173 [250], 64 Cu-labelled anti-AXL antibody [251], antibody-based agents such as the antibody-drug conjugate (ADC) AXL-107-MMAE [252] and AXL-specific CAR and SynNotch receptor [253], which have also shown promising results in preclinical studies.…”

Section: Axl-targeted Therapiesmentioning

confidence: 99%

AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications

2019

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Molecular targeted therapy for cancer has been a research hotspot for decades. AXL is a member of the TAM family with the high-affinity ligand growth arrest-specific protein 6 (GAS6). The Gas6/AXL signalling pathway is associated with tumour cell growth, metastasis, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, drug resistance, immune regulation and stem cell maintenance. Different therapeutic agents targeting AXL have been developed, typically including small molecule inhibitors, monoclonal antibodies (mAbs), nucleotide aptamers, soluble receptors, and several natural compounds. In this review, we first provide a comprehensive discussion of the structure, function, regulation, and signalling pathways of AXL. Then, we highlight recent strategies for targeting AXL in the treatment of cancer.AXL-targeted drugs, either as single agents or in combination with conventional chemotherapy or other small molecule inhibitors, are likely to improve the survival of many patients. However, future investigations into AXL molecular signalling networks and robust predictive biomarkers are warranted to select patients who could receive clinical benefit and to avoid potential toxicities.

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Section: Axl-targeted Therapiesmentioning

confidence: 99%

AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications

2019

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“…Recently, Axl has been exploited as a target for immune therapy. For example, anti-Axl chimeric antigen receptor (CAR)–T-cell therapy was used to kill Axl-positive myelogenous leukemia cells and TNBC cells with promising efficacy [121, 122]. Axl has also been investigated as a target for antibody drug conjugates (ADCs).…”

Section: Axl As a Therapeutic Targetmentioning

confidence: 99%

Does Axl have potential as a therapeutic target in pancreatic cancer?

Brekken

2018

Expert Opinion on Therapeutic Targets

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Introduction: Pancreatic cancer is a leading cause of cancer-related death. Metastasis, therapy resistance, and immunosuppression are dominant characteristics of pancreatic tumors. Strategies that enhance the efficacy of standard of care and/or immune therapy are likely the most efficient route to improve overall survival in this disease. Areas covered: Axl, a member of the TAM (Tyro3, Axl, MerTK) family of receptor tyrosine kinases, is involved in cell plasticity, chemoresistance, immune suppression, and metastasis in various cancers, including pancreatic cancer. This review provides an overview of Axl and its function in normal conditions, summarizes the regulation and function of Axl in cancer, and highlights the contribution of Axl to pancreatic cancer as well as its potential as a therapeutic target. Expert opinion: Axl is an attractive therapeutic target in pancreatic cancer because it contributes to many of the roadblocks that hamper therapeutic efficacy. Clinical evidence supporting Axl inhibition in pancreatic cancer is currently limited; however, multiple clinical trials have been initiated or are in the planning phase to test the effect of inhibiting Axl in conjunction with standard therapy in pancreatic cancer patients. We anticipate that these studies will provide robust validation of Axl as a therapeutic target in pancreatic cancer.

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“…To demonstrate that T cells customized with AsNRs are potential tools for cancer treatment, we adjusted the downstream program and replaced the reporter with blinatumomab ( Fig. 7a) 13,35 . Blinatumomab is a monoclonal antibody, an α-CD19/CD3 bispecific T-cell engager (BiTE), that directs CD3 + T cells to attack CD19 + tumor cells 36,37 .…”

Section: Resultsmentioning

confidence: 99%

Using apelin-based synthetic Notch receptors to detect angiogenesis and treat solid tumors

Wang

Zhong

et al. 2020

Nat Commun

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Angiogenesis is a necessary process for solid tumor growth. Cellular markers for endothelial cell proliferation are potential targets for identifying the vasculature of tumors in homeostasis. Here we customize the behaviors of engineered cells to recognize Apj, a surface marker of the neovascular endothelium, using synthetic Notch (synNotch) receptors. We designed apelin-based synNotch receptors (AsNRs) that can specifically interact with Apj and then stimulate synNotch pathways. Cells engineered with AsNRs have the ability to sense the proliferation of endothelial cells (ECs). Designed for different synNotch pathways, engineered cells express different proteins to respond to angiogenic signals; therefore, angiogenesis can be detected by cells engineered with AsNRs. Furthermore, T cells customized with AsNRs can sense the proliferation of vascular endothelial cells. As solid tumors generally require vascular support, AsNRs are potential tools for the detection and therapy of a variety of solid tumors in adults.

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Engineering Axl specific CAR and SynNotch receptor for cancer therapy

Cited by 47 publications

References 28 publications

AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications

AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications

Does Axl have potential as a therapeutic target in pancreatic cancer?

Using apelin-based synthetic Notch receptors to detect angiogenesis and treat solid tumors

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