Multi-parameter flow cytometric quantitation of the expression of the tumor-associated antigen SM3 in normal and neoplastic ovarian tissues. A comparison with HMFG1 and HMFG2

Dam, Peter van; Jobling, Thomas W.; Shepherd, John H.; Lowe, David; Watson, James V.; Chard, Tim

doi:10.1002/1097-0142(19910701)68:1<169::aid-cncr2820680130>3.0.co;2-r

Cited by 11 publications

(5 citation statements)

References 34 publications

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“…The SM3 Ab has renowned selectivity for tumor-associated MUC1 (1,4,5,11). To generate a MUC1-specific CAR (S28z), an SM3 scFv was fused to sequences derived from CD28 and CD3 (Fig.…”

Section: The Igd Hinge Improves Retargeting Capacity Of Muc1-specificmentioning

confidence: 99%

“…First, owing to transcriptional up-regulation (2) elevated levels are found in many tumors, notably of the breast and ovary (3,4). Second, whereas MUC1 is normally confined to the luminal epithelium, polarity of expression is lost upon transformation (5).…”

mentioning

confidence: 99%

“…Owing to altered glycosyltransferase expression (6, 7), tumor-associated MUC1 contains a preponderance of shorter glycans including Tn, sialyl Tn (STn), T (ThomsenFriedenreich), and ST (6 -9). Underglycosylation of MUC1 unmasks cryptic epitopes within the VNTR, enabling tumor-selective binding by several Abs (3,4,10,11).…”

mentioning

confidence: 99%

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Retargeting of Human T Cells to Tumor-Associated MUC1: The Evolution of a Chimeric Antigen Receptor

Wilkie

Picco²,

Foster

et al. 2008

The Journal of Immunology

295

243

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MUC1 is a highly attractive immunotherapeutic target owing to increased expression, altered glycosylation, and loss of polarity in >80% of human cancers. To exploit this, we have constructed a panel of chimeric Ag receptors (CAR) that bind selectively to tumor-associated MUC1. Two parameters proved crucial in optimizing the CAR ectodomain. First, we observed that the binding of CAR-grafted T cells to anchored MUC1 is subject to steric hindrance, independent of glycosylation status. This was overcome by insertion of the flexible and elongated hinge found in immunoglobulins of the IgD isotype. Second, CAR function was highly dependent upon strong binding capacity across a broad range of tumor-associated MUC1 glycoforms. This was realized by using an Ab-derived single-chain variable fragment (scFv) cloned from the HMFG2 hybridoma. To optimize CAR signaling, tripartite endodomains were constructed. Ultimately, this iterative design process yielded a potent receptor termed HOX that contains a fused CD28/OX40/CD3ζ endodomain. HOX-expressing T cells proliferate vigorously upon repeated encounter with soluble or membrane-associated MUC1, mediate production of proinflammatory cytokines (IFN-γ and IL-17), and elicit brisk killing of MUC1+ tumor cells. To test function in vivo, a tumor xenograft model was derived using MDA-MB-435 cells engineered to coexpress MUC1 and luciferase. Mice bearing an established tumor were treated i.p. with a single dose of engineered T cells. Compared with control mice, this treatment resulted in a significant delay in tumor growth as measured by serial bioluminescence imaging. Together, these data demonstrate for the first time that the near-ubiquitous MUC1 tumor Ag can be targeted using CAR-grafted T cells.

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“…The SM3 Ab has renowned selectivity for tumor-associated MUC1 (1,4,5,11). To generate a MUC1-specific CAR (S28z), an SM3 scFv was fused to sequences derived from CD28 and CD3 (Fig.…”

Section: The Igd Hinge Improves Retargeting Capacity Of Muc1-specificmentioning

confidence: 99%

mentioning

confidence: 99%

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Retargeting of Human T Cells to Tumor-Associated MUC1: The Evolution of a Chimeric Antigen Receptor

Wilkie

Picco²,

Foster

et al. 2008

The Journal of Immunology

295

243

View full text Add to dashboard Cite

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“…MUC1 is a large transmembrane glycoprotein that is transcriptionally upregulated in breast and ovarian tumors [ 130 , 131 ]. MUC1 expression is confined to normal luminal epithelium, and the expression is lost upon transformation [ 132 – 136 ].…”

Section: Current Clinical Targets For Solid Tumorsmentioning

confidence: 99%

The expansion of targetable biomarkers for CAR T cell therapy

Townsend

Shrestha

Robison

et al. 2018

J Exp Clin Cancer Res

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Biomarkers are an integral part of cancer management due to their use in risk assessment, screening, differential diagnosis, prognosis, prediction of response to treatment, and monitoring progress of disease. Recently, with the advent of Chimeric Antigen Receptor (CAR) T cell therapy, a new category of targetable biomarkers has emerged. These biomarkers are associated with the surface of malignant cells and serve as targets for directing cytotoxic T cells. The first biomarker target used for CAR T cell therapy was CD19, a B cell marker expressed highly on malignant B cells. With the success of CD19, the last decade has shown an explosion of new targetable biomarkers on a range of human malignancies. These surface targets have made it possible to provide directed, specific therapy that reduces healthy tissue destruction and preserves the patient’s immune system during treatment. As of May 2018, there are over 100 clinical trials underway that target over 25 different surface biomarkers in almost every human tissue. This expansion has led to not only promising results in terms of patient outcome, but has also led to an exponential growth in the investigation of new biomarkers that could potentially be utilized in CAR T cell therapy for treating patients. In this review, we discuss the biomarkers currently under investigation and point out several promising biomarkers in the preclinical stage of development that may be useful as targets.

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“…Samples were analysed using a FACScan flow cytometer (Becton Dickinson, Oxford, UK) to detect fluorochromic staining of DNA (Fluorescence 2) and for c-met (Fluorescence 1). For data analysis, cell debris, cell clumps, and lymphocytes were excluded by setting appropriate gates based on forward scatter, side scatter, and DNA profiles of breast samples and lymphocytes[22]. Optimal conditions for c-met staining were determined by analysis of HT 29 cell line (positive control) and lymphocytes (negative control,Fig.…”

mentioning

confidence: 99%

Expression and loss of heterozygosity of c‐met proto‐oncogene in primary breast cancer

Nagy

Clark

Cooke

et al. 1995

Journal of Surgical Oncology

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The c-met proto-oncogene encodes the receptor to hepatocyte growth factor-scatter factor (HGF-SF), a mesenchyme-derived cytokine with cell-dissociating, invasion, and angiogenic properties. The expression of c-met in breast cancer is the subject of controversy; 111 primary breast cancers were examined for LOH of c-met by Southern blot electrophoresis. c-met expression was measured in a further 40 patients with breast cancer and in 8 patients with benign breast disease by flow cytometry. LOH of c-met was detected in only 4% of informative breast cancers. Expression of c-met was significantly greater in patients with breast cancer than in those with benign breast disease (P < 0.01, Mann-Whitney). There was no correlation however between increased c-met expression and clinicopathological prognostic variables. These results do not support the role of c-met as a tumour suppressor gene in breast cancer but suggest increased receptor expression in malignant breast disease. The significance of this increased expression in breast cancer is the subject of further investigation.

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Multi-parameter flow cytometric quantitation of the expression of the tumor-associated antigen SM3 in normal and neoplastic ovarian tissues. A comparison with HMFG1 and HMFG2

Cited by 11 publications

References 34 publications

Retargeting of Human T Cells to Tumor-Associated MUC1: The Evolution of a Chimeric Antigen Receptor

Retargeting of Human T Cells to Tumor-Associated MUC1: The Evolution of a Chimeric Antigen Receptor

The expansion of targetable biomarkers for CAR T cell therapy

Expression and loss of heterozygosity of c‐met proto‐oncogene in primary breast cancer

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