UPenn Osteosarcoma Vaccine Trial Open!

Immunotherapy with a HER2 targeting Listeria induces HER2-specific immunity and demonstrates potential therapeutic effects in a phase I trial in canine osteosarcoma

Nicola J. Mason et al, UPenn (Author Manuscript Published OnlineFirst on March 18, 2016; DOI: 10.1158/1078-0432.CCR-16-0088)

Abstract:

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 (OSA), a well recognized spontaneous model for pediatric OSA, 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.

Comments: This pilot study documented that ADXS31-164 after limb amputation and 4 doses of carboplatin chemotherapy is effective (prolongs disease free interval-DFI- and survival times-ST) in dogs with HER2/neu+OSA when compared to a historical control group. Most of the dogs had tolerable adverse effects.  For the 18 dogs with no evidence of metastatic disease at enrollment, the median DFI was 615 days and the MST was 956 days. Overall survival rates at 1, 2 and 3 years for dogs treated with ADXS31-164 after amputation and carboplatin chemotherapy were 77.8%, 67% and 56% respectively. These results compare favorably with multiple studies evaluating dogs with OSA treated with amputation plus carboplatin, where reported DFIs ranged from 123-257 days, MSTs ranged from 207–321 days (30-34) and overall survival rates at 1 and 2 years were 35.4% and 10- 15% respectively.

No signalment (breed, age, sex) is provided in the manuscript, but I know some of the dogs were Greyhounds. The catch: the tumor must test positive for HER2/neu, a special stain done using a biopsy or amputation specimen. Dr. Mason is currently enrolling dogs for this study; dogs must live in PA, CT, NY, DE, MD, NJ, CA, AZ, NV (http://www.vet.upenn.edu/research/clinical-trials/penn-vet-clinical-trials/clinical-trial/clinical-trial-using-immunotherapy-for-dogs-with-osteosarcoma).