Purpose:Recombinant Listeria vaccines induce tumor-specific T cell responses that eliminate established tumors and prevent metastatic disease in murine cancer models. We used dogs with HER2/neu+ appendicular osteosarcoma, a well recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human HER2/neu fusion protein (ADXS31-164) could safely induce HER2/neu specific immunity and prevent metastatic disease. Experimental Design: Eighteen dogs that underwent limb amputation or salvage surgery and adjuvant chemotherapy were enrolled in a phase I dose escalation clinical trial and received either 2 x 108, 5 x 108, 1 x 109 or 3.3 x 109 CFU of ADXS31-164 intravenously every 3 weeks for 3 administrations. Results: Only low grade, transient toxicities were observed. ADXS31-164 broke peripheral tolerance and induced antigen-specific IFN-γ responses against the intracellular domain of HER2/neu in 15/18 dogs within 6 months of treatment. Furthermore, ADXS31-164 reduced the incidence of metastatic disease and significantly increased duration of survival time and 1, 2 and 3 year survival rates when compared to a historical control group with HER2/neu+ appendicular osteosarcoma treated with amputation and chemotherapy alone. Conclusions:These findings demonstrate that ADXS31-164 administered in the setting of minimal residual disease, can induce HER2/neu specific immunity and may reduce the incidence of metastatic disease and prolong overall survival in a clinically relevant, spontaneous, large animal model of cancer. These findings therefore, have important translational relevance for children with osteosarcoma and adults with other HER2/neu+ cancers.
- Received January 11, 2016.
- Revision received March 4, 2016.
- Accepted March 7, 2016.
- Copyright ©2016, American Association for Cancer Research.