Breast Cancer

Biography

Biography: Nicola Mason

Abstract

HER2/neu is a membrane bound receptor tyrosine kinase belonging to the erbB family. ErbB2 gene amplification and HER2/ neu over-expression is reported in 30-40% of patients with mammary carcinoma and serves as an important immune therapeutic target. HER2/neu is also expressed in 40% of pediatric osteosarcoma patients and we have found similar HER2 expression in pet dogs with spontaneous osteosarcoma (OSA). We have taken advantage of this naturally occurring spontaneous HER2+ tumor in dogs to evaluate the safety and efficacies of a recombinant Listeria expressing a chimeric human HER2/neu (Lm-LLO-cHuHer2) to generate potent HER2-specific T cell mediated immunity and prevent metastatic disease after standard of care amputation and chemotherapy. Administration of 3 doses of Lm-LLO-cHuHer2 at three-week intervals was found to be safe and effective at prolonging progression free survival and overall survival in dogs. Side effects that occurred were low grade and transient. IFN-γELISpot analysis revealed that Lm-LLO-cHuHer2 was able to break tolerance to HER2/neu supporting the hypothesis that HER2 specific T cell mediated immunity was preventing disease relapse. A second clinical trial was performed on dogs whose owners elected not to perform amputation or chemotherapy to determine the effects of combination radiotherapy and Lm-LLO-cHuHer2 immunotherapy on primary HER2+ appendicular OSA. Dogs received 16 Gyradiation, delivered as 2 fractions on consecutive days to the primary tumor site. Dogs then received a total of 8 doses of Lm-LLO-cHuHer2 administered intravenously at 3-week intervals and were then monitored for acute and chronic toxicities, primary tumor progression and development of metastatic disease. We found that repeat administrationsofLm-LLO-cHuHer2 were safe, broke tolerance to HER2/neu, delayed the progression of the primary tumor and delayed/prevented metastatic disease. In conclusion, we show that systemic administration ofLm-LLO-HER2/neuis well tolerated, breaks tolerance to HER2/neu, can prevent metastatic disease when administered in the setting of minimal residual disease, and can act synergistically with RT on HER2+ bone lesions to delay disease progression. These findings may have important translational relevance for human patients with HER2+ cancers such as mammary carcinoma.