Abstract
Abstract The purpose of this study is to determine the safety and efficacy of a highly attenuated recombinant Listeria monocytogenes expressing a chimeric human HER2/neu (Lm-LLO-HER2/neu) in combination with palliative radiation (RT) to induce HER2 specific immunity and delay tumor progression in dogs with spontaneous osteosarcoma (OSA). Dogs develop OSA that recapitulates many aspects of human OSA, and are recognized as a clinically relevant, large animal model in which to evaluate novel therapies. Previously we have shown that Lm-LLO-HER2/neu administration to dogs with HER2+ OSA following amputation and chemotherapy is safe, breaks tolerance to HER2 and prolongs overall survival. Ten systemically healthy dogs with histopathologically confirmed, treatment naïve, HER2+ appendicular OSA, and no evidence of cardiac or metastatic disease were enrolled. All dogs received 2 × 8Gy fractions of RT on consecutive days, followed by the first of 8 intravenous doses of Lm-LLO-HER2/neu given once every 3 weeks. Dogs were monitored at each treatment and every 2 months after for systemic and cardiac toxicity, lameness and quality of life (QOL) (using a validated owner questionnaire). Radiographs were performed at baseline, week 10, week 22 and every 2 months thereafter to determine the effect on the primary tumor and development of pulmonary metastases. PBMCs were collected every 3 weeks to evaluate HER2/neu specific T cell responses. The primary endpoint was time to progression; secondary end points were safety and overall survival. Results are compared to historical canine controls that received 2 × 8Gy RT alone. Repeat Lm-LLO-HER2/neu administration was well tolerated with no systemic or cardiac toxicity. Lameness and QOL showed near uniform improvement over the study period. To date, limb radiographs of 7 dogs have been taken 10 weeks post enrollment and showed no evidence of tumor progression. 4 dogs have currently completed the scheduled 8 vaccinations, and limb radiographs of these dogs taken at 22 weeks, showed no progression of the primary lesion. At the time of writing, 4/10 dogs have died; 2 dogs were euthanized due to pathological fracture, and 2 dogs were euthanized due to metastatic disease. One dog, still alive, has developed pulmonary metastatic disease. At the time of writing, median time to progression is 243 days and median survival time (MST) is 285 days. Historically, MST of dogs treated with RT alone is 136 days. Results of IFN-γ ELISpot assays are pending. To conclude, our preliminary results show repeat Lm-LLO-HER2/neu administration is safe and well tolerated with no cardiac toxicity. Our results also suggest that combination RT and Lm-LLO-HER2/neu immunotherapy improves QOL, delays primary tumor progression and prolongs overall survival in canine OSA. These findings may have important translational relevance for human patients with OSA and other HER2/neu+ cancers. Citation Format: Nicola Mason, Josephine Gnanandarajah, Danielle Laughlin, Julie Engiles, Anu Wallecha, Yvonne Paterson. Recombinant HER2/Neu expressing Listeria combined with radiation safely delays tumor progression and prolongs overall survival in a phase I clinical study in canine osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-113. doi:10.1158/1538-7445.AM2015-LB-113
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.