Journal
CANCER IMMUNOLOGY RESEARCH
Volume 1, Issue 3, Pages 179-189Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-13-0001
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Funding
- NIH
- Basser Research Center for BRCA in the Abramson Cancer Center at the University of Pennsylvania
- Ruth L. Kirschstein National Research Service Award [5T32CA115299-07]
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High levels of human telomerase reverse transcriptase (hTERT) are detected in more than 85% of human cancers. Immunologic analysis supports that hTERT is a widely applicable target recognized by T cells and can be potentially studied as a broad cancer immunotherapeutic, 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 (NHP). When delivered by electroporation, phTERT elicited strong, broad hTERT-specific CD8 T-cell responses including induction of T cells expressing CD107a, IFN-gamma, and TNF-alpha in mice. The ability of phTERT to overcome tolerance was evaluated in an NHP model, whose TERT is 96% homologous to that of hTERT. Immunized monkeys exhibited robust [ average 1,834 spot forming unit (SFU)/10(6) peripheral blood mononuclear cells (PBMC)], diverse (multiple immunodominant epitopes) IFN-gamma responses and antigen-specific perforin release (average 332 SFU/10(6) PBMCs), suggesting that 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. Finally, in vivo cytotoxicity assay confirmed that phTERT-induced CD8 T cells exhibited specific cytotoxic T lymphocyte (CTL) activity, capable of eliminating hTERT-pulsed target cells. These findings support that this synthetic electroporation-delivered DNA phTERT may have a role as a broad therapeutic cancer vaccine candidate. (C) 2013 AACR.
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