Volume 2 Supplement 3
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
© Gnanandarajah et al.; licensee BioMed Central Ltd. 2014
Published: 6 November 2014
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.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.