repost from kyle.ramer on the Yahoo mesage board Published OnlineFirst July 17...inovio has been busy
Highly optimized DNA vaccine targeting human telomerase reverse transcriptase stimulates potent antitumor immunity
Jian Yan1, Panyupa Pankhong2, Thomas H Shin2, Nyamekye Obeng-Adjei2, Matthew P Morrow3, Jewell N Walters2, Amir S Khan3, Niranjan Y. Sardesai3, and David B Weiner2,*
- Author Affiliations
1Research and Development, Inovio Pharmaceuticals, Inc.
2Department of Pathology and Laboratory Medicine, University of Pennsylvania
3Product Development, Inovio Pharmaceuticals, Inc.
?* Corresponding Author:
David B Weiner, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 422 Curie Boulevard, Philadelphia, PA, United States dbweiner@mail.med.upenn.edu
Abstract
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-? and TNF-a 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-? 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. Published OnlineFirst July 17, 2013; doi: 10.1158/2326-6066.CIR-13-0001
Copyright © 2013, American Association for Cancer Research.
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