Toxicology and efficacy of tumor-targeting Salmonella typhimurium A1-R compared to VNP 20009 in a syngeneic mouse tumor model in immunocompetent mice

// Yong Zhang 1 , Wenluo Cao 1, 2 , Makoto Toneri 1, 2 , Nan Zhang 1 , Tasuku Kiyuna 1, 2 , Takashi Murakami 1, 2 , Scott D. Nelson 3 , Sarah M. Dry 3 , Yunfeng Li 3 , Shukuan Li 1 , Xiaoen Wang 1 , Huaiyu Ma 1 , Arun S. Singh 4 , Fritz C. Eilber 5 , Robert M. Hoffman 1, 2 and Ming Zhao 1 1 AntiCancer, Inc., San Diego, California, USA 2 Department of Surgery, University of California, San Diego, California, USA 3 Department of Pathology, University of California, Los Angeles, California, USA 4 Department of Hematology/Oncology, University of California, Los Angeles, California, USA 5 Division of Surgical Oncology, University of California, Los Angeles, California, USA Correspondence to: Ming Zhao, email: all@anticancer.com Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: Salmonella typhimurium A1-R, VNP20009, toxicity, tumor targeting, biodistribution Received: March 01, 2017 Accepted: March 21, 2017 Published: May 03, 2017 ABSTRACT Salmonella typhimurium A1-R ( S. typhimurium A1-R) attenuated by leu and arg auxotrophy has been shown to target multiple types of cancer in mouse models. In the present study, toxicologic and biodistribution studies of tumor-targeting S. typhimurium A1-R and S. typhimurium VNP20009 (VNP 20009) were performed in a syngeneic tumor model growing in immunocompetent BALB/c mice. Single or multiple doses of S. typhimurium A1-R of 2.5 × 10 5 and 5 × 10 5 were tolerated. A single dose of 1 × 10 6 resulted in mouse death. S. typhimurium A1-R (5 × 10 5 CFU) was eliminated from the circulation, liver and spleen approximately 3-5 days after bacterial administration via the tail vein, but remained in the tumor in high amounts. S. typhimurium A1-R was cleared from other organs much more rapidly. S. typhimurium A1-R and VNP 20009 toxicity to the spleen and liver was minimal. S. typhimurium A1-R showed higher selective targeting to the necrotic areas of the tumors than VNP20009. S. typhimurium A1-R inhibited the growth of CT26 colon carcinoma to a greater extent at the same dose of VNP20009. In conclusion, we have determined a safe dose and schedule of S. typhimurium A1-R administration in BALB/c mice, which is also efficacious against tumor growth. The results of the present report indicate similar toxicity of S. typhimurium A1-R and VNP20009, but greater antitumor efficacy of S. typhimurium A1-R in an immunocompetent animal. Since VNP2009 has already proven safe in a Phase I clinical trial, the present results indicate the high clinical potential of S. typhimurium A1-R.