Skip to main content

Volume 2 Supplement 3

Abstracts of the 29th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC)

  • Poster presentation
  • Open access
  • Published:

A recombinant HER2/neu expressing listeria monocytogenes (Lm-LLO) immunotherapy delays metastatic disease and prolongs overall survival in a spontaneous canine model of osteosarcoma - a Phase I clinical trial

Osteosarcoma (OSA) is an aggressive mesenchymal bone tumor that affects ~3000 children annually in the USA. Treatment consists of chemotherapy, radiotherapy and radical surgery. Despite treatment, metastatic disease is common and results in 30-40% mortality within 5 years. Novel therapies that prevent metastatic disease are required to improve outcome. HER2/Neu is a tyrosine kinase receptor belonging to the EGFR family. It is expressed in ~40% of pediatric OSA and is linked to reduced chemotherapeutic response, high metastatic rates and short overall survival time. Recent reports indicate that HER2/Neu is expressed on OSA tumor initiating cells and that immune targeting of HER2/Neu delays metastatic disease.

Large breed dogs spontaneously develop OSA that recapitulates many aspects of pediatric OSA including histologic heterogeneity, aggressive local disease and early metastases. At diagnosis, 95% of dogs have micrometastatic disease and despite amputation and chemotherapy, the median survival time is 10 months with most dogs euthanized due to progressive metastatic disease. As in pediatric OSA, HER2/Neu is expressed in ~40% of canine appendicular OSA making dogs a relevant model to evaluate the effects of HER2/Neu targeted immune therapy on metastatic disease prevention.

We performed a Phase I clinical trial to evaluate the safety and efficacy of an attenuated, recombinant Listeria monocytogenes (Lm) expressing a chimeric human HER2/Neu fusion protein (ADXS31-164) to prevent metastatic disease in dogs with HER2/Neu+ appendicular OSA. Lm secretes a pore-forming lysin, listeriolysin O (LLO) that enables it to escape the phagosome and access the class I processing machinery of antigen-presenting cells. As such, recombinant Listeria, engineered to express tumor antigens fused to LLO, induce potent tumor-specific CD8 T cells that mediate tumor regression in murine models. Seventeen dogs with HER2/Neu+ OSA that had undergone amputation and carboplatin chemotherapy received 1 × 108, 5 × 108, 1 × 109 or 3 × 109 CFU of ADXS31-164 intravenously every 3 weeks for three administrations. ADXS31-164-associated toxicities were low grade and transient. Treated dogs failed to develop pulmonary metastatic disease and showed a statistically significant increase in overall survival compared to a historical HER2/Neu+ control group. 14/17 treated dogs are still alive; median survival in HER2/Neu+ control dogs (n = 13) was 316 days (p = 0.032). ELISpot assays are underway to evaluate ADXS31-164-associated HER2/Neu specific immune responses. Our results indicate that ADXS31-164 significantly delays metastatic disease in a clinically relevant, spontaneous model and have important implications for pediatric OSA.

Author information

Authors and Affiliations

Authors

Rights and permissions

Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gnanandarajah, J.S., Ndikuyeze, G.H., Engiles, J.B. et al. A recombinant HER2/neu expressing listeria monocytogenes (Lm-LLO) immunotherapy delays metastatic disease and prolongs overall survival in a spontaneous canine model of osteosarcoma - a Phase I clinical trial. j. immunotherapy cancer 2 (Suppl 3), P55 (2014). https://doi.org/10.1186/2051-1426-2-S3-P55

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/2051-1426-2-S3-P55

Keywords