Prognostic significance of 5T4 oncofetal antigen expression in colorectal carcinoma

Starzyńska, Teresa; Marsh, P J; Schofield, Philip F.; Roberts, Stephen A; Myers, Kevin A.; Stern, Peter L.

doi:10.1038/bjc.1994.173

Cited by 111 publications

(77 citation statements)

References 23 publications

(15 reference statements)

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“…Transduction of the 5T4 cDNA into cell lines enhances cell motility and reduces cell -cell contacts suggesting that it may be mechanistically involved in the malignant phenotype (Carsberg et al, 1996). This is further supported by evidence that expression of 5T4 correlates with poorer survival in colorectal carcinoma (Starzynska et al, 1994). This protein has only limited expression in normal adult human tissues (Southall et al, 1990) making it a useful target for the immunotherapy of cancer.…”

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confidence: 82%

“…The pattern of staining was also characterised as either stromal, tumour membranous or tumour cytoplasmic. This categorisation was used based on the previous patterns of staining noted in colorectal and gastric carcinomas (Starzynska et al, 1994). All positive samples however, clearly demonstrated a membranous staining pattern ( Figure 1A) and there was no evidence of stromal staining on any of the tumour specimens.…”

Section: T4 Expression On Rcc Biopsiesmentioning

confidence: 99%

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Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

et al. 2005

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The 5T4 oncofoetal antigen is a heavily glycosylated cell surface protein found on human placental trophoblast and on diverse types of human cancer but is not expressed at significant levels on adult human tissues in health. It therefore satisfies the criteria for a tumour-associated antigen and is an ideal target for the immunotherapy of cancer. We report here that 5T4 is strongly expressed on the majority of renal cell carcinomas and therefore this population of patients is suitable for trials of 5T4-targeted therapies. In particular, we have shown that T cells from renal cell carcinoma patients can be genetically modified to kill 5T4 expressing renal cancer cell lines by introduction of a chimeric-signalling protein. This protein consists of a single chain antibody fragment capable of binding antigen directly at the cell surface and then activating the T cell by virtue of a CD3z-signalling domain. This is a powerful tool that bypasses a number of mechanisms that allow tumours to escape T-cell killing and can be readily scaled up for clinical use.

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mentioning

confidence: 82%

Section: T4 Expression On Rcc Biopsiesmentioning

confidence: 99%

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

et al. 2005

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“…Expression of 5T4 is associated with advanced disease and/or worse clinical outcome in NSCLC and gastric, colorectal, and ovarian carcinomas (8,(15)(16)(17). 5T4 was shown to modulate CXCR4 function (18) and Wnt signaling (19), yet its specific function remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Sapra

Damelin

DiJoseph

et al. 2013

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumorinitiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo antitumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathologic complete response in each model with doses as low as 3 mg antibody/kg dosed every 4 days. In a non-small cell lung cancer patient-derived xenograft model, in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors, such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered to cynomolgus monkeys at doses up to 10 mg antibody/kg/ cycle Â 2 and displayed a half-life of 5 days. The preclinical efficacy and safety data established a promising therapeutic index that supports clinical testing of A1mcMMAF. Mol Cancer Ther; 12(1); 38-47. Ó2012 AACR.

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“…5T4 is expressed by a wide spectrum of cancers but is not detected on most normal adult tissues (19,20). In colorectal, gastric, and ovarian carcinomas, h5T4 expression is associated with poorer clinical outcome (21)(22)(23). The restricted expression of 5T4 on tumor tissues, as well as its association with tumor progression, makes it a promising new candidate for immunotherapy.…”

Section: Combination Of Vaccination and Chimeric Receptor Expressing mentioning

confidence: 99%

Combination of Vaccination and Chimeric Receptor Expressing T Cells Provides Improved Active Therapy of Tumors

Jiang

Gilham

Mulryan

et al. 2006

The Journal of Immunology

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We have generated murine T cells expressing chimeric immune receptors (CR) against human 5T4 oncofetal Ag (h5T4) and evaluated their tumor therapeutic efficacy alone and in combination with immunization using a replication-defective adenovirus encoding h5T4 (Rad.h5T4) and bone marrow-derived dendritic cells (BMDC). The h5T4-specific engineered T cells demonstrated Ag-specific, non-MHC-restricted cytolysis of h5T4-positive B16 and CT26 tumor cells in vitro by cytotoxicity assay and antitumor activity in vivo using a Winn assay. In the s.c. injected B16h5T4 melanoma model, early local but not systemic i.v. administration of syngeneic h5T4-specific CR T cells significantly increased mice survival. This improvement was further enhanced when combined with immunization with Rad.h5T4, followed by post-CR T cell treatment with BMDC in the active therapy model, possibly through mechanisms of enhancing Ag-specific cellular immune responses. This synergistic effect was lost without delivery of the BMDC. Our findings suggest that combining engineered T cells with specific vaccination strategies can improve the active tumor therapy.

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Prognostic significance of 5T4 oncofetal antigen expression in colorectal carcinoma

Cited by 111 publications

References 23 publications

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Combination of Vaccination and Chimeric Receptor Expressing T Cells Provides Improved Active Therapy of Tumors

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