Chimeric antigen receptor-modified T Cells inhibit the growth and metastases of established tissue factor-positive tumors in NOG mice

Zhang, Qing; Li, Ang; Li, Huizhong; Xǔ, Jǐnjīng; Tian, Kui; Yang, Jie; Zheng, Junnian

doi:10.18632/oncotarget.14367

Cited by 21 publications

(21 citation statements)

References 40 publications

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“…Intratumoral administration of TF-CAR T cells demonstrated significant inhibition of the growth of TF-positive NSCLC xenografts in vivo . In addition, TF-CAR T cells’ ability to suppress TF-positive NSCLC metastasis was revealed in a pulmonary metastasis model of the same mice 153 .…”

Section: Driving Mutationsmentioning

confidence: 99%

“…CAR T cells can recognize antigens independently of human leukocyte antigen (HLA) unlike to the physiology of T cells and have the ability to affect tumor cells with low HLA expression or with the “wrong” antigen 152 . Tissue factor (TF) or coagulation factor III is overexpressed in many cancer types including LC 153 . The therapeutic efficacy of TF-CAR T cells has been estimated in a subcutaneous xenograft model in NOG mice using the human NSCLC cell line NCI-H292 containing the gene encoding luciferase (NCI-H292-luc).…”

Section: Driving Mutationsmentioning

confidence: 99%

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Cell death-based treatment of lung adenocarcinoma

2018

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The most common type of lung cancer is adenocarcinoma (ADC), comprising around 40% of all lung cancer cases. In spite of achievements in understanding the pathogenesis of this disease and the development of new approaches in its treatment, unfortunately, lung ADC is still one of the most aggressive and rapidly fatal tumor types with overall survival less than 5 years. Lung ADC is often diagnosed at advanced stages involving disseminated metastatic tumors. This is particularly important for the successful development of new approaches in cancer therapy. The high resistance of lung ADC to conventional radiotherapies and chemotherapies represents a major challenge for treatment effectiveness. Here we discuss recent advances in understanding the molecular pathways driving tumor progression and related targeted therapies in lung ADCs. In addition, the cell death mechanisms induced by different treatment strategies and their contribution to therapy resistance are analyzed. The focus is on approaches to overcoming drug resistance in order to improve future treatment decisions.

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Section: Driving Mutationsmentioning

confidence: 99%

Section: Driving Mutationsmentioning

confidence: 99%

Cell death-based treatment of lung adenocarcinoma

2018

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“…In a xenograft model, these CAR-T blocked the growth and metastasis of TF-positive lung cancer cells. 159 To address potential on-target off-tumor toxicities in TF expressing healthy tissues, the murine FVII was used, which, unlike human FVII, possesses equivalent binding to hTF and mTF. No apparent toxicities were observed.…”

Section: Immunoconjugatesmentioning

confidence: 99%

Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

Rondon

Kroone

Kapteijn

et al. 2019

Semin Thromb Hemost

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It has been long-established that cancer and thrombosis are linked, but the exact underlying pathological mechanism remains to be unraveled. As the initiator of the coagulation cascade, the transmembrane glycoprotein tissue factor (TF) has been intensely investigated for its role in cancer-associated thrombosis and cancer progression. TF expression is regulated by both specific oncogenes and environmental factors, and it is shown to regulate primary growth and metastasis formation in a variety of cancer models. In clinical studies, TF has been shown to be overexpressed in most cancer types and is strongly associated with disease progression. While TF clearly associates with cancer progression, a prominent role for TF in the development of cancer-associated thrombosis is less clear. The current concept is that cancer-associated thrombosis is associated with the secretion of tumor-derived TF-positive extracellular vesicles in certain tumor types. To date, many therapeutic strategies to target TF—both in preclinical and clinical phase—are being pursued, including targeting TF or the TF:FVIIa complex by itself or by exploiting TF as a docking molecule to deliver cytotoxic compounds to the tumor. In this review, the authors summarize the current understanding of the role of TF in both cancer progression and cancer-associated thrombosis, and discuss novel insights on TF as a therapeutic target as well as a biomarker for cancer progression and VTE.

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“…Similar to our previous idea of the use of murine fVII single chain peptide 27,28,35 and light chain 14 to target murine and human TF, a published study used murine fVII light chain in construction of TF-targeting CAR T cells (CD8 hinge and transmembrane followed by CD28, 4-1BB and CD3ζ) 60 . In the design and development of TF-targeting CAR, I chose human fVII light chain, the natural ligand for TF, instead of full length human fVII, partial sequence of murine fVII, full length antibody or antibody fragments (e.g., scFv) against TF, as the recognition domain for TF for the following reasons.…”

Section: Discussionmentioning

confidence: 97%

Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer

2020

Sci Rep

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Triple-negative breast cancer (TNBC), representing ~15% of globally diagnosed breast cancer, is typically an incurable malignancy due to the lack of targetable surface targets for development of effective therapy. To address the unmet need for TNBC treatment, we recently determined that tissue factor (TF) is a useful surface target in 50-85% of patients with TNBC and developed a secondgeneration TF-targeting antibody-like immunoconjugate (called L-ICON) for preclinical treatment of TNBC. Using the chimeric antigen receptor (CAR) approach, here we develop and test TF-targeting CARengineered natural killer (TF-CAR-NK) cells that co-express CD16, the Fc receptor (FcγIII) to mediate antibody-dependent cellular toxicity (ADCC), for a preclinical assessment of immunotherapy of TNBC using TF-CAR-NK cell as single agent therapy and in combination with L-ICON. Our preclinical results demonstrate that TF-CAR-NK cells alone could kill TNBC cells and its efficacy was enhanced with L-ICON ADCC in vitro. Moreover, TF-CAR-NK cells were effective in vivo for the treatment of tnBc in cell lineand patient's tumor-derived xenograft mouse models. Thus, this study established the proof of concept of targeting TF as a new target in CAR-NK immunotherapy for effective treatment of TNBC and may warrant further preclinical study and potentially future investigation in TNBC patients.The adoptive transfer of chimeric antigen receptor (CAR)-expressing T and natural killer (NK) cells represents a novel cancer immunotherapy approach. The concept of the CAR is based upon the idea of expressing novel receptors on the T or NK cell surface that would enable the T and NK cell to identify corresponding antigens on the surface of a target cell. The basic CAR construct consists of an extracellular antigen-recognition domain, usually single-chain antibody variable fragments (scFv), attached to an extracellular spacer domain, a transmembrane domain of CD28 and a signaling cytoplasmic domain such as 4-1BB (CD137), OX40 (CD134), DAP10, ICOS and CD3zeta chain (CD3ζ). The most advanced application is the use of CAR-T cells targeting CD19, a surface antigen on B cell malignancies, which has demonstrated antitumor efficacy in patients with these cancers 1 . However, early-phase clinical trials of CAR T therapy also showed that this treatment is frequently associated with side effects 1 , some even causing life-threatening toxicity 2 , partly due to the fact that current CAR targets are expressed by both the malignant cells and normal cells, such as CD19, which is also expressed by normal B cells throughout the B cell lineage 1 . Also, one of the major challenges in CAR therapy is the heterogeneity of tumor antigens, for instance, antigen loss or low antigen density on the cancer cells 3 . To overcome these challenges, it would be ideal to develop CAR T or CAR NK cells that could target a surface molecule that is commonly yet selectively expressed by several major tumor compartments, including but not limited to, the cancer cell, cancer stem cell (CSC) and tum...

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Chimeric antigen receptor-modified T Cells inhibit the growth and metastases of established tissue factor-positive tumors in NOG mice

Cited by 21 publications

References 40 publications

Cell death-based treatment of lung adenocarcinoma

Cell death-based treatment of lung adenocarcinoma

Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer

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