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      Bacteria-cancer interactions: bacteria-based cancer therapy

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          Abstract

          Recent advances in cancer therapeutics, such as targeted therapy and immunotherapy, have raised the hope for cures for many cancer types. However, there are still ongoing challenges to the pursuit of novel therapeutic approaches, including high toxicity to normal tissue and cells, difficulties in treating deep tumor tissue, and the possibility of drug resistance in tumor cells. The use of live tumor-targeting bacteria provides a unique therapeutic option that meets these challenges. Compared with most other therapeutics, tumor-targeting bacteria have versatile capabilities for suppressing cancer. Bacteria preferentially accumulate and proliferate within tumors, where they can initiate antitumor immune responses. Bacteria can be further programmed via simple genetic manipulation or sophisticated synthetic bioengineering to produce and deliver anticancer agents based on clinical needs. Therapeutic approaches using live tumor-targeting bacteria can be applied either as a monotherapy or in combination with other anticancer therapies to achieve better clinical outcomes. In this review, we introduce and summarize the potential benefits and challenges of this anticancer approach. We further discuss how live bacteria interact with tumor microenvironments to induce tumor regression. We also provide examples of different methods for engineering bacteria to improve efficacy and safety. Finally, we introduce past and ongoing clinical trials involving tumor-targeting bacteria.

          Cancer: tumor-targeting bacteria enter the anticancer arsenal

          Live tumor-targeting bacteria can selectively induce cancer regression and, with the help of genetic engineering, be made safe and effective vehicles for delivering drugs to tumor cells. In a review article, Jung-Joon Min and colleagues from Chonnam National University Medical School in Hwasun, South Korea, discuss the clinical history of using natural or engineered bacterial strains to suppress cancer growth. Because bacteria such as Salmonella and Listeria preferentially home in on tumors or their surrounding microenvironments, researchers have harnessed these microbial agents to attack cancer cells without causing collateral damage to normal tissues. Bioengineers have also armed bacteria with stronger tumor-sensing and more targeted drug delivery capabilities, and improved control of off-target toxicities. An increasing number of therapeutic bacterial strains are now entering clinical testing, promising to enhance the efficacy of more conventional anticancer treatments.

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          Most cited references163

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          The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas.

          In 1891, William B. Coley injected streptococcal organisms into a patient with inoperable cancer. He thought that the infection he produced would have the side effect of shrinking the malignant tumor. He was successful, and this was one of the first examples of immunotherapy. Over the next forty years, as head of the Bone Tumor Service at Memorial Hospital in New York, Coley injected more than 1000 cancer patients with bacteria or bacterial products. These products became known as Coley's Toxins. He and other doctors who used them reported excellent results, especially in bone and soft-tissue sarcomas. Despite his reported good results, Coley's Toxins came under a great deal of criticism because many doctors did not believe his results. This criticism, along with the development of radiation therapy and chemotherapy, caused Coley's Toxins to gradually disappear from use. However, the modern science of immunology has shown that Coley's principles were correct and that some cancers are sensitive to an enhanced immune system. Because research is very active in this field, William B. Coley, a bone sarcoma surgeon, deserves the title "Father of Immunotherapy".
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            Synchronized cycles of bacterial lysis for in vivo delivery

            The pervasive view of bacteria as strictly pathogenic has given way to an appreciation of the widespread prevalence of beneficial microbes within the human body 1–3 . Given this milieu, it is perhaps inevitable that some bacteria would evolve to preferentially grow in environments that harbor disease and thus provide a natural platform for the development of engineered therapies 4–6 . Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ 7–10 . Here, we engineer a clinically relevant bacterium to lyse synchronously at a threshold population density and to release genetically encoded cargo. Following quorum lysis, a small number of surviving bacteria reseed the growing population, thus leading to pulsatile delivery cycles. We use microfluidic devices to characterize the engineered lysis strain and we demonstrate its potential as a drug delivery platform via co-culture with human cancer cells in vitro. As a proof of principle, we track the bacterial population dynamics in ectopic syngeneic colorectal tumors in mice. The lysis strain exhibits pulsatile population dynamics in vivo, with mean bacterial luminescence that remained two orders of magnitude lower than an unmodified strain. Finally, guided by previous findings that certain bacteria can enhance the efficacy of standard therapies 11 , we orally administer the lysis strain, alone or in combination with a clinical chemotherapeutic, to a syngeneic transplantation model of hepatic colorectal metastases. We find that the combination of both circuit-engineered bacteria and chemotherapy leads to a notable reduction of tumor activity along with a marked survival benefit over either therapy alone. Our approach establishes a methodology for leveraging the tools of synthetic biology to exploit the natural propensity for certain bacteria to colonize disease sites.
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              Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer.

              GVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity. © 2015 by American Society of Clinical Oncology.
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                Author and article information

                Contributors
                +82-61-379-2876 , jjmin@jnu.ac.kr , jjminmd@gmail.com
                Journal
                Exp Mol Med
                Exp. Mol. Med
                Experimental & Molecular Medicine
                Nature Publishing Group UK (London )
                1226-3613
                2092-6413
                11 December 2019
                11 December 2019
                December 2019
                : 51
                : 12
                : 152
                Affiliations
                [1 ]ISNI 0000 0001 0356 9399, GRID grid.14005.30, Laboratory of In vivo Molecular Imaging, Institute for Molecular Imaging and Theranostics, , Chonnam National University Medical School and Hwasun Hospital, ; Jeonnam, 58128 Republic of Korea
                [2 ]ISNI 0000 0001 0356 9399, GRID grid.14005.30, Department of Molecular Medicine (BrainKorea21 Plus), , Chonnam National University Graduate School, ; Gwangju, 61469 Republic of Korea
                [3 ]ISNI 0000 0001 0356 9399, GRID grid.14005.30, Department of Nuclear Medicine, , Chonnam National University Medical School, ; Jeonnam, 58128 Republic of Korea
                Article
                297
                10.1038/s12276-019-0297-0
                6906302
                31827064
                8655a835-0bcb-4642-8df7-8ca8c0e39ace
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 12 March 2019
                : 19 April 2019
                : 30 April 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003725, National Research Foundation of Korea (NRF);
                Award ID: NRF-2017R1A2B3012157
                Award ID: NRF-2017R1A2B3012157
                Award ID: NRF-2017R1A2B3012157
                Award ID: NRF-2017R1A2B3012157
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2019

                Molecular medicine
                cancer,cancer therapy
                Molecular medicine
                cancer, cancer therapy

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