CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth

Zhuang, Xiaodong; Maione, Federica; Robinson, J. A.; Bentley, Michael D.; Kaul, Baksho; Whitworth, Katharine; Jumbu, Neeraj; Jinks, Elizabeth; Byström, Jonas; Gabriele, P.; Garibaldi, E.; Delmastro, Elena; Nagy, Zsuzsanna; Gilham, David E.; Giraudo, Enrico; Bicknell, Roy; Lee, Steven P.

doi:10.1172/jci.insight.138808

Cited by 23 publications

(18 citation statements)

References 54 publications

(65 reference statements)

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“…All these functions induced by FN-EDA might be elicited through its binding to the integrins α4β1, α4β7, 59 α9β1, 60 α5β1 61 or to TLR4 62 displaying a direct protumorigenic activity. 63 64 Other CAR-T cells attempt to disrupt tumor neovasculature by targeting α5β3 integrin, 65 TEM8 66 67 or CLEC14A, 68 although some toxicity issues have been also arisen 67 69 probably because of the 'on-target off-tumor' activity of the CAR-T.…”

Section: Discussionmentioning

confidence: 99%

Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells

Martín-Otal¹,

Lasarte-Cía²,

Serrano³

et al. 2022

J Immunother Cancer

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BackgroundOne of the main difficulties of adoptive cell therapies with chimeric antigen receptor (CAR)-T cells in solid tumors is the identification of specific target antigens. The tumor microenvironment can present suitable antigens for CAR design, even though they are not expressed by the tumor cells. We have generated a CAR specific for the splice variant extra domain A (EDA) of fibronectin, which is highly expressed in the tumor stroma of many types of tumors but not in healthy tissues.MethodsEDA expression was explored in RNA-seq data from different human tumor types and by immunohistochemistry in paraffin-embedded tumor biopsies. Murine and human anti-EDA CAR-T cells were prepared using recombinant retro/lentiviruses, respectively. The functionality of EDA CAR-T cells was measured in vitro in response to antigen stimulation. The antitumor activity of EDA CAR-T cells was measured in vivo in C57BL/6 mice challenged with PM299L-EDA hepatocarcinoma cell line, in 129Sv mice-bearing F9 teratocarcinoma and in NSG mice injected with the human hepatocarcinoma cell line PLC.ResultsEDA CAR-T cells recognized and killed EDA-expressing tumor cell lines in vitro and rejected EDA-expressing tumors in immunocompetent mice. Notably, EDA CAR-T cells showed an antitumor effect in mice injected with EDA-negative tumor cells lines when the tumor stroma or the basement membrane of tumor endothelial cells express EDA. Thus, EDA CAR-T administration delayed tumor growth in immunocompetent 129Sv mice challenged with teratocarcinoma cell line F9. EDA CAR-T treatment exerted an antiangiogenic effect and significantly reduced gene signatures associated with epithelial-mesenchymal transition, collagen synthesis, extracellular matrix organization as well as IL-6-STAT5 and KRAS pathways. Importantly, the human version of EDA CAR, that includes the human 41BB and CD3ζ endodomains, exerted strong antitumor activity in NSG mice challenged with the human hepatocarcinoma cell line PLC, which expresses EDA in the tumor stroma and the endothelial vasculature. EDA CAR-T cells exhibited a tropism for EDA-expressing tumor tissue and no toxicity was observed in tumor bearing or in healthy mice.ConclusionsThese results suggest that targeting the tumor-specific fibronectin splice variant EDA with CAR-T cells is feasible and offers a therapeutic option that is applicable to different types of cancer.

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Section: Discussionmentioning

confidence: 99%

Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells

Martín-Otal¹,

Lasarte-Cía²,

Serrano³

et al. 2022

J Immunother Cancer

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“…Several potential targets have been identified, associated with tumor endothelial cells and stroma, and used to generate antibody-drug conjugates or CAR-T cell-based strategies for cancer therapy [ 133 , 134 , 135 , 136 , 137 , 138 ]. CD276 (B7-H3) is an appealing target.…”

Section: Discussionmentioning

confidence: 99%

Alternative Vascularization Mechanisms in Tumor Resistance to Therapy

Belotti

Pinessi

Taraboletti

2021

Cancers

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Blood vessels in tumors are formed through a variety of different mechanisms, each generating vessels with peculiar structural, molecular, and functional properties. This heterogeneity has a major impact on tumor response or resistance to antineoplastic therapies and is now emerging as a promising target for strategies to prevent drug resistance and improve the distribution and efficacy of antineoplastic treatments. This review presents evidence of how different mechanisms of tumor vessel formation (vasculogenesis, glomeruloid proliferation, intussusceptive angiogenesis, vasculogenic mimicry, and vessel co-option) affect tumor responses to antiangiogenic and antineoplastic therapies, but also how therapies can promote alternative mechanisms of vessel formation, contributing to tumor recurrence, malignant progression, and acquired drug resistance. We discuss the possibility of tailoring treatment strategies to overcome vasculature-mediated drug resistance or to improve drug distribution and efficacy.

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“…PLVAP has been associated with cancer, traumatic spinal cord injury, acute ischemic encephalopathy, graft glomerulopathy, Norrie disease, and diabetic retinopathy (31). CLEC14A is a glycoprotein that is selectively overexpressed in the vascular system of many solid human tumors, and as such has attracted considerable attention as a target antigen (32). Earlier studies found that CLEC14A may be a tumor endothelial marker (33).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis reveals biomarkers with cancer stem cell characteristics in kidney renal clear cell carcinoma

Zhang¹,

Xiong²,

Zhang³

et al. 2021

Transl Androl Urol

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Background: Kidney renal clear cell carcinoma (KIRC) is a renal cortical tumor. KIRC is the most common subtype of kidney cancer, accounting for 70-80% of kidney cancer. Early identification of the risk of KIRC patients can facilitate more accurate clinical treatment, but there is a lack of effective prognostic markers. We aimed to identify new prognostic biomarkers for KIRC on the basis of the cancer stem cell (CSC) theory.Methods: RNA-sequencing (RNA-seq) data and related clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Weighted gene co-expression network analysis (WGCNA) was used to identify significant modules and hub genes, and predictive hub genes were used to construct prognostic characteristics. Results:The messenger RNA expression-based stemness index (mRNAsi) in tumor tissues of patients in the TCGA database is higher than that of the corresponding normal tissues. In addition, some clinical features and results are highly correlated with mRNAsi. WGCNA found that the green module is the most prominent module associated with mRNAsi; the genes in the green module are mainly concentration in Notch binding, endothelial cell development, Notch signaling pathway, and Rap 1 signaling pathway. A protein-protein interaction (PPI) network showed that the top 10 central genes were significantly associated with the transcriptional level. Moreover, the 10 hub genes were up-regulated in KIRC. Regarding survival analysis, the nomogram of the prognostic markers of the seven pivotal genes showed a higher predictive value. The classical receiver operating characteristic (ROC) curve analysis showed that risk score biomarkers had the highest accuracy and specificity with an area under the curve (AUC) value of 0.701. Conclusions: mRNAsi-related genes may be good prognostic biomarkers for KIRC.

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CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth

Cited by 23 publications

References 54 publications

Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells

Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells

Alternative Vascularization Mechanisms in Tumor Resistance to Therapy

Bioinformatics analysis reveals biomarkers with cancer stem cell characteristics in kidney renal clear cell carcinoma

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