Evaluations of CRC2631 toxicity, tumor colonization, and genetic stability in the TRAMP prostate cancer model.

Robert A Kazmierczak,Clintin P Davis-Stober,Austen A Barnett,Bakul Dhagat-Mehta,Li Lee,Elke Gulden,Lixin Ma,Yves C Chabu

doi:10.18632/oncotarget.27769

Robert A Kazmierczak, Clintin P Davis-Stober + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.27769

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Abstract

Conventional cancer chemotherapies are not fully efficacious and do not target tumors, leading to significant treatment-related morbidities. A number of genetically attenuated cancer-targeting bacteria are being developed to safely target tumors in vivo. Here we report the toxicological, tumor-targeting, and efficacy profiles of Salmonella enterica serovar Typhimurium CRC2631 in a syngeneic and autochthonous TRAMP model of aggressive prostate cancer. CRC2631 preferentially colonize primary and metastatic tumors in the TRAMP animals. In addition, longitudinal whole genome sequencing studies of CRC2631 recovered from prostate tumor tissues demonstrate that CRC2631 is genetically stable. Moreover, tumor-targeted CRC2631 generates an anti-tumor immune response. Combination of CRC2631 with checkpoint blockade reduces metastasis burden. Collectively, these findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies.

Highlights

Conventional cancer chemotherapies are not specific and, as such, generate significant morbidities [1, 2]
VNP20009 is considered as the safety benchmark in bacterial cancer therapy development because it has been safely administered in human cancer patients [7, 30]
To control for tumor burden, groups of fourteen-week-old C57BL/6Tg(TRAMP)8247Ng/J x FvBNHsd mice (B6FVB) Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) (+) mice were scanned by magnetic resonance imaging (MRI) and assigned either to the CRC2631 (N = 4) or the VNP20009 (N = 4) group

Summary

Introduction

Conventional cancer chemotherapies are not specific and, as such, generate significant morbidities [1, 2]. The majority of VNP20009 preclinical studies relied on data derived from minimally aggressive tumors in immune-compromised animals [4,5,6], raising translatability concerns. VNP20009 showed moderate toxicity but no anti-tumor effect in the aforementioned clinical studies [7], presumably because it was rapidly cleared by patients’ immune system. These studies have provided significant clinical insights and www.oncotarget.com have underscored the need for cancer-targeting biologics that are safe and efficacious, and likely to translate to the clinic

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Conclusion