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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy
R W Griffiths1, D E Gilham, A Dangoor
1Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Research Centre, Manchester M20 4BX, UK.
Abstract:
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 CD3zeta-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.
Insights
The 5T4 antigen is present on most kidney cancers, making it a target for immunotherapy. Genetically modified T cells can now kill 5T4-expressing renal cell carcinoma cells.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- The 5T4 oncofoetal antigen is a cell surface glycoprotein expressed on placental trophoblasts and various human cancers.
- 5T4 is not significantly expressed in healthy adult tissues, positioning it as a potential tumor-associated antigen.
- This antigen is a promising target for cancer immunotherapy strategies.
Purpose of the Study:
- To investigate the expression of the 5T4 antigen in renal cell carcinoma (RCC).
- To evaluate the potential of 5T4-targeted therapies for RCC treatment.
- To demonstrate the efficacy of genetically engineered T cells against 5T4-expressing RCC.
Main Methods:
- Immunohistochemical analysis to determine 5T4 expression in RCC.
- Development of chimeric antigen receptors (CARs) for T cell modification.
- In vitro co-culture assays to assess T cell-mediated killing of RCC cell lines.
Main Results:
- 5T4 is highly expressed on the majority of renal cell carcinomas.
- Genetically modified T cells, equipped with a chimeric-signalling protein targeting 5T4, effectively killed 5T4-expressing RCC cell lines.
- The engineered T cells utilized a single-chain antibody fragment and a CD3zeta-signalling domain to bind and activate T cells.
Conclusions:
- The 5T4 antigen is a suitable target for immunotherapy in a significant proportion of renal cell carcinoma patients.
- Engineered T cells offer a potent approach to overcome tumor immune evasion mechanisms.
- This T cell-based therapy is scalable for clinical application in cancer treatment.
