High levels of human Telomerase Reverse Transcriptase (hTERT) are detected in over 85% of human cancers. Immunological analysis supports hTERT is a widely applicable target recognized by T cells and can be potentially studied as a broad cancer immune therapeutic, or a unique line of defense against tumor recurrence. There remains an urgent need to develop more potent hTERT vaccines. Here, a synthetic highly optimized full-length hTERT DNA vaccine (phTERT) was designed and the induced immunity was examined in mice and non-human primates. When delivered by electroporation, phTERT elicited strong, broad hTERT-specific CD8 responses including induction of T-cells expressing CD107a, IFN-γ and TNF-α in mice. The ability of phTERT to overcome tolerance was evaluated in a NHP model, whose TERT is 96% homologous to that of hTERT. Immunized monkeys exhibited robust (average 1834 SFU/106 PBMCs), diverse (multiple immunodominant epitopes) IFN-γ responses and antigen-specific perforin release (average 332 SFU/106 PBMCs), suggesting phTERT breaks tolerance and induces potent cytotoxic responses in this human relevant model. Moreover, in an HPV16-associated tumor model, vaccination of phTERT slows tumor growth and improves survival rate in both prophylactic and therapeutic studies. Lastly, in vivo cytotoxicity assay confirmed that phTERT-induced CD8 T cells exhibited specific CTL activity, capable of eliminating hTERT-pulsed target cells. These findings support that this synthetic EP-delivered DNA phTERT may have a role as a broad therapeutic cancer vaccine candidate.
- Received January 21, 2013.
- Revision received May 29, 2013.
- Accepted July 11, 2013.
- Copyright © 2013, American Association for Cancer Research.