The ends of chromosomes are protected from degradation by regions of repetitive DNA called telomeres (figure 1). They are gradually degraded as a cell divides until eventually they are too short to permit further cell division. This limit on replicative capacity is overcome by nearly all cancer cells by expressing hTERT (telomerase). hTERT is normally only expressed by a small subset of normal cells that must divide indefinitely such as hematopoietic stem cells . hTERT extends the telomeres maintaining their length following repeated cell divisions.
|Figure 1: Condensed chromosome pair with telomeres highlighted in pink. Credit: AJC PHOTOGRAPHY. No changes were made. Creative Commons Attribution-ShareAlike 2.0.|
In normal cells immunogenic hTERT is presented at the cell surface by major histocompatibility proteins HLA which induces immune system tolerance to prevent autoimmunity. This presents a problem for vaccine design. There are however alternative hTERT peptides that are called cryptic which are presented at the cell surface but not recognised by T-cells due to their low affinity for HLA and so the immune system is blind to them. This can be used to the advantage of vaccine production. It has been found that adding a tyrosine to the end of a cryptic peptide increases its affinity for HLA-A2.1 but does not alter its conformation . These optimised cryptic peptides can then be used as a vaccine that triggers T-cells to attack tumour cells expressing high levels of hTERT.
The safety profile of a hTERT vaccine needs careful consideration due to the potential to induce autoimmunity. Preclinically there has been no evidence of this, however clinical considerations may become more clear upon completion of phase II studies .
- Vonderheide, Robert H. ‘Prospects and Challenges of Building a Cancer Vaccine Targeting Telomerase’. Biochimie 90, no. 1 (January 2008): 173–80. doi:10.1016/j.biochi.2007.07.005.
- Tourdot, S., A. Scardino, E. Saloustrou, D. A. Gross, S. Pascolo, P. Cordopatis, F. A. Lemonnier, and K. Kosmatopoulos. ‘A General Strategy to Enhance Immunogenicity of Low-Affinity HLA-A2. 1-Associated Peptides: Implication in the Identification of Cryptic Tumor Epitopes’. European Journal of Immunology 30, no. 12 (December 2000): 3411–21. doi:10.1002/1521-4141
- ‘Efficacy Study of Vx001 Vaccine in NSCLC Patients – Full Text View – ClinicalTrials.gov’. Accessed 4 March 2016. https://clinicaltrials.gov/ct2/show/NCT01935154?term=Vx-001&rank=1.