Immunotherapy with a HER2-Targeting Listeria Induces HER2-Specific Immunity and Demonstrates Potential Therapeutic Effects in a Phase I Trial in Canine Osteosarcoma

Clin Cancer Res. 2016 Sep 1;22(17):4380-90. doi: 10.1158/1078-0432.CCR-16-0088. Epub 2016 Mar 18.


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 × 10(8), 5 × 10(8), 1 × 10(9), or 3.3 × 10(9) 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 IFNγ responses against the intracellular domain of HER2/neu in 15 of 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 with 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. Clin Cancer Res; 22(17); 4380-90. ©2016 AACR.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Animals
  • Biomarkers
  • Bone Neoplasms / veterinary*
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / adverse effects
  • Cancer Vaccines / immunology*
  • Disease Progression
  • Dog Diseases / diagnosis
  • Dog Diseases / immunology*
  • Dog Diseases / mortality
  • Dog Diseases / therapy*
  • Dogs
  • Immunity, Cellular
  • Immunization Schedule
  • Immunotherapy* / methods
  • Interferon-gamma
  • Listeria / immunology*
  • Osteosarcoma / veterinary*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / immunology
  • Treatment Outcome
  • Vaccination
  • Vaccines, Synthetic


  • Biomarkers
  • Cancer Vaccines
  • Vaccines, Synthetic
  • Interferon-gamma
  • Receptor, ErbB-2