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

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 þ 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 Â 10 8 , 5 Â 10 8 , 1 Â 10 9 , or 3.3 Â 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 antigenspecific IFNg 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 þ 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 þ cancers.

Analysis of outcome in dogs that undergo secondary amputation as an end‐point for managing complications related to limb salvage surgery for treatment of appendicular osteosarcoma

“…This is thought to be related to enhanced innate immunity related to natural killer cells and macrophages. This has resulted in increased interest in this field as a potential therapeutic target . Clinical solutions for chronic, severe or non‐salvageable complications following limb salvage surgery are limited, and therefore complications often lead to amputation of the affected limb (secondary amputation).…”

NCR1 Expression Identifies Canine Natural Killer Cell Subsets with Phenotypic Similarity to Human Natural Killer Cells

“…Canines provide an outbred, immune competent disease model with genetic heterogeneity and a shared environment with humans (1–4). Testing of novel therapies in the canine model has educated the protocols for bone marrow transplants in humans and, more recently, has been used for the testing of immune therapies such as adoptive transfer of T-cells, HER2- Listeria vaccine, and Liposomal-muramyl tripeptide (L-MTP-PE; mifamurtide) (5–12). …”

Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma

“…Furthermore, the prognosis is particularly dire for humans and dogs with gross metastatic disease . Therefore, novel therapeutics designed to target a variety of host immune cells and enhance the anti‐tumour immune response are being investigated in both species for their activity in OSA …”