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Development of a live and highly attenuated Listeria monocytogenes-based vaccine for the treatment of Her2/neu-overexpressing cancers in human

Cancer Gene Therapy volume 18, pages 53–62 (2011)Cite this article

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Abstract

A chimeric human Her2/neu gene (ChHer2) harboring most of the known major histocompatibility complex class I epitopes of the HER2/neu oncogene was expressed as a fusion protein to a non-hemolytic fragment of listeriolysin O (LLO), by the highly attenuated Listeria vector LmddA, which lacks antibiotic selection markers and the ability to spread from cell-to-cell. This construct (ADXS31–164) was tested for immunogenicity and anti-tumor effects in mice. Despite being highly attenuated, ADXS31–164 proved to be efficacious in breaking immune tolerance toward the HER2/neu self-antigen. ADXS31–164 elicited strong T-cell immune responses in experimental animals. In tumors, ADXS31–164 caused a reduction in regulatory T cells (Treg) accompanied by an increase in the CD8+/Treg ratio. Comparison of this vaccine with the conventional antibiotic resistant Listeria vector (Lm-LLO-ChHer2) shows that ADXS31–164 is more efficacious in delaying tumor growth in Her2/neu transgenic animals. Because of its well-defined attenuation mechanism and independence from antibiotic selection markers, ADXS31–164 is potentially more suitable for human use. These results support the future clinical development of this vaccine for the treatment of HER2/neu-overexpressing malignancies, such as breast, colorectal and pancreatic cancers.

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Acknowledgements

The imaging data presented here was performed at the Optical Imaging Core (supported in part by NIH Grant CA105008) of the Small Animal Imaging Facility at the University of Pennsylvania. We are also grateful to Dr Yingqui Yvette Liu and Dr Wafik S El-Deiry for their advice and assistance on the part of the optical imaging study.

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Authors and Affiliations

  1. Advaxis Inc., Research and Development, New Brunswick, NJ, USA

    V Shahabi, P C Maciag, S Rivera & A Wallecha

  2. Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    M M Seavey

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  1. V Shahabi
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Correspondence to A Wallecha.

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Competing interests

Advaxis Inc. is a for-profit vaccine and therapeutic company that has licensed or has an option to license all patents from the University of Pennsylvania that concern the use of Lms or listerial products as vaccines. The following authors have a financial interest in Advaxis Inc., and thus may have a conflict of interest: Drs PC Maciag, A Wallecha, S Rivera and V Shahabi. Dr MM Seavey declares no conflict of interest.

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Shahabi, V., Seavey, M., Maciag, P. et al. Development of a live and highly attenuated Listeria monocytogenes-based vaccine for the treatment of Her2/neu-overexpressing cancers in human. Cancer Gene Ther 18, 53–62 (2011). https://doi.org/10.1038/cgt.2010.48

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