Low dose chemotherapy combined with attenuated Salmonella decreases tumor burden and is less toxic than high dose chemotherapy in an autochthonous murine model of breast cancer

Abstract

BackgroundImmunotherapies for cancer treatment have demonstrated substantial promise even though toxicities and development of tumor resistance limit their effectiveness. A combinatorial approach using immunotherapy with other treatment modalities may decrease side effects while maintaining maximal therapeutic effect. We aimed to determine if bacterial immunotherapy in combination with a chemotherapeutic would be efficacious and less toxic than conventional chemotherapy in an established, preclinical, autochthonous tumor model. MethodsBALB-neuT mice develop autochthonous mammary neoplasms that resemble closely the aggressive Her2-driven cancer found in human patients. Virulence-attenuated S. Typhimurium was used for bacterial immunotherapy. Doxorubicin was the chemotherapeutic agent used at the maximum tolerated dose (5 mg/kg) and low dose (1.25 mg/kg). S. Typhimurium was administered intravenously on day 0 and doxorubicin on days 0, 7, and 14. Experiments concluded on day 35. Mammary pad tumors were measured weekly to ascertain efficacy, and mice were weighed weekly to evaluate toxicity. ResultsMice administered maximum tolerated dose doxorubicin (5 mg/kg) demonstrated a 1.4-fold increase in tumor size by day 35 and showed a nearly 25% weight loss by day 14 revealing severe toxicity. When mice were administered a single dose of S. Typhimurium combined with a low dose of doxorubicin (1.25 mg/kg), tumors increased <3-fold by day 35, and mice showed only 5% weight loss, indicating no clinically relevant toxicity. ConclusionBacterial immunotherapy combined with low dose chemotherapy decreased the tumor burden when compared with low dose chemotherapy alone and was less toxic than maximum tolerated dose chemotherapy in an established, autochthonous murine model of breast cancer.