Rationale for UV1 as an hTERT Therapeutic Cancer Vaccine
Based on available blood samples from long term cancer survivors with several types of cancer who had been treated with different forms of telomerase Therapeutic Cancer Vaccine and hTERT transfected Dendritic Cells a new set of peptide epitopes from hTERT were defined. T-cell reactivity against these peptides both forms spontaneously in some patients and could be triggered by immunotherapy. The fact that T-cell responses to these peptides were only observed in patients with an extraordinary clinical course indicates that they could be responsible for tumor eradication in these patients. Subsequently, three of these newly identified peptides were selected for further characterization and clinical development as UV1. The peptides give a broad immune response across HLA types and no pre-screening of patient HLA type is needed.
Mode of action of UV1
TCV’s are designed to exploit professional antigen presenting cells (APCs) to initiate immune responses against “foreign” material. Thus, if APCs in the skin are exposed to synthetic peptides corresponding to peptide degradation products associated with cancer, the APCs will present the therapeutic TCV peptides/HLA complexes to T cells, which will be activated in the lymph nodes. The activated T-cells will circulate in the body to search for tumour cells displaying peptide/HLA complexes (identical to the complexes presented to them by the APCs) and cancer cells will be killed when they are detected by the activated T-cells.
In order for T-cells to be able to kill tumour cells, the tumour cells must process tumour associated proteins and present the resulting peptide epitopes to the T-cells in the context of HLA molecules. In the case of UV1, it is anticipated that induction of immune responses against these tumour-associated epitopes will result in tumour cell killing, providing clinical benefits in patients suffering from telomerase expressing tumours. Moreover, it is expected that telomerase specific T-helper cells induced by UV1 will be re-stimulated in-situ at the tumour site by APCs presenting telomerase peptides from digested cancer cells. This local re-stimulation may further result in epitope spreading (i.e. activation of CTLs recognizing a range of peptide epitopes presented on the surface of the cancer cells;
By using long TCV peptides, T-helper (Th) cells are stimulated. These cells play a complex role in the tumour microenvironment and are able to interact directly with tumour cells and a number of immune effectors, leading to tumour cell destruction. Dead tumour cells release more antigen which in turn is taken up by antigen presenting cells, stimulating a second wave of T-cell immunity targeting other tumour antigens, a phenomenon called “epitope spreading”. This process is essential to achieve clinical success with a peptide TCV strategy. The figure above is a illustration of the mode of action of UV1 (however over simplified and omitting other….important elements of the role of the Th-cell including several types of co-stimulatory cell surface molecules and interactions with many other cell types.