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Tumor volume ratio. Bar graphs show the tumor volume ratio (post-treatment volume/pretreatment volume). S. typhimurium A1-R suppressed tumor growth significantly compared to the untreated group (P ¼ 0.001). There was also a significant difference between the S. typhimurium A1-R group and the imatinib group (P ¼ 0.013). Imatinib did not show significant efficacy compared to the untreated control (P ¼ 0.462). N ¼ 6 mice/group. Error bars: AESD.
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Gastrointestinal stromal tumor (GIST) is a refractory disease in need of novel efficacious therapy. The aim of our study was to evaluate the effectiveness of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) using on a patient derived orthotopic xenograft (PDOX) model of imatinib-resistant GIST. The GIST was obtained from a patient...
Context in source publication
Context 1
... to imatinib on the GIST PDOX. We established the GIST PDOX model using surgical orthotopic implantation in the anterior gastric wall (Fig. 1). The schematic treatment design is shown in Fig. 2. Three weeks after S. typhimurium A1-R injection, tumor volumes in each group were weighted. The estimated tumor volume ratio (day 22/day 0) is provided in Fig. ...
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Background
Gastrointestinal stromal tumors (GISTs) extremely and rarely metastasize to the skin, and such metastases have not been well characterized.
Methods
Retrospective analysis of clinicopathological data of patients with skin metastasis of a GIST (SM-GIST) admitted to Xiangya Hospital (Changsha, Hunan, China) and literature review were condu...
A jejunal gastrointestinal stromal tumour (GIST) is a rare neoplasm of the gastrointestinal tract. Massive bleeding due to a jejunal GIST is a diagnostic challenge and could present as a life-threatening situation needing urgent intervention. A 54-year-old woman presented with episodes of melaena and haematochezia for the previous 3 days. An oesoph...
Citations
... 14 Subsequently, multiple attenuated bacterial species have been tested for cancer treatment; strains include Clostridium, S. Typhimurium, Bifidobacterium, Escherichia coli, and Listeria. [15][16][17][18][19][20][21][22][23] We have recently shown that schwannoma is a good candidate for bacterial immunotherapy; this is the first reported use of bacteria for the treatment of a benign neoplasm. 24 Our data demonstrated that intratumoral (i.t.) injection of attenuated S. Typhimurium strain VNP20009 controlled tumor growth in both human xenograft and mouse syngeneic schwannoma models. ...
Schwannomas are slow-growing benign peripheral nerve sheath tumors derived from Schwann-lineage cells that develop in association with NF2-related schwannomatosis (NF2) and schwannomatosis (NF3), as well as spontaneously. Individuals affected with NF2 and NF3 have multiple schwannomas with tumors arising throughout life. Surgical resection, the standard management, is limited in scope and efficacy and is itself associated with significant morbidity. We have previously shown that direct intratumoral injection of attenuated Salmonella Typhimurium (S. Typhimurium), strain VNP20009, showed a potent anti-tumor effect in preclinical NF-2 schwannoma models. The United States Federal Drug Administration (FDA) requires that bacterial products utilized in clinical trials be produced without exposure to animal-derived-products. In this context, we developed, characterized, and tested the antitumor efficacy of an attenuated S. Typhimurium serially passaged in animal-product-free media, naming it VNP20009-AF for “VNP20009-animal-product-free.” Our in vitro data did not indicate any significant changes in the viability, motility, or morphology of VNP20009-AF, compared to its parental strain. In vivo efficacy data demonstrated that VNP20009-AF and VNP20009 controlled tumor growth to the same degree in both human NF2-schwannoma xenograft and murine-NF2 schwannoma allograft models. Together, these data support the use of VNP20009-AF for the translation of bacterial schwannoma therapy into clinical trials.
... In the mid-1800s, William Coley introduced bacterial cancer therapy (BCT) using live Streptococcus pyogenes to treat solid tumors (8). Some bacterial strains, including Salmonella typhimurium (9)(10)(11)(12), specifically home to and proliferate within hypoxic areas of angiogenic tumors, inducing direct lysis of tumor cells and antitumor immune responses (13). Furthermore, bacterial injection of tumors inhibits angiogenesis (14), shifts tumoral macrophages from M2 (tumor promoting) to M1 (tumoricidal) types (11,15), and induces antitumor adaptive immunity (16). ...
Schwannomas are slow-growing benign neoplasms that develop throughout the body causing pain, sensory/motor dysfunction, and death. Because bacterial immunotherapy has been used in the treatment of some malignant neoplasms, we evaluated attenuated Salmonella typhimurium strains as immunotherapies for benign murine schwannomas. Several bacterial strains were tested, including VNP20009, a highly attenuated strain that was previously shown to be safe in human subjects with advanced malignant neoplasms, and a VNP20009 mutant that was altered in motility and other properties that included adherence and invasion of cultured mammalian cells. VNP20009 controlled tumor growth in two murine schwannoma models and induced changes in cytokine and immune effector cell profiles that were consistent with induction of enhanced innate and adaptive host immune responses compared with controls. Intratumoral (i.t.) injection of S. typhimurium led to tumor cell apoptosis, decreased tumor angiogenesis, and lower growth of the injected schwannoma tumors. Invasive VNP20009 was significantly more efficacious than was a noninvasive derivative in controlling the growth of injected tumors. Bacterial treatment apparently induced systemic antitumor immunity in that the growth of rechallenge schwannomas implanted following primary bacterial treatment was also reduced. Checkpoint programmed death-1 (PD-1) blockade induced by systemic administration of anti-PD-1 antibodies controlled tumor growth to the same degree as i.t. injection of S. typhimurium, and together, these two therapies had an additive effect on suppressing schwannoma growth. These experiments represent validation of a bacterial therapy for a benign neoplasm and support development of S. typhimurium VNP20009, potentially in combination with PD-1 inhibition, as a schwannoma immunotherapy.
... PDOX models of sarcoma behave quite similar to patient sarcoma, including recurrence after surgery [22], metastasis [24] and invasive growth to surrounding tissue [20,22]. The sarcoma PDOX models present the opportunity to test multiple therapeutic agents that are potentially active [20,26,29,33,37,43,45,48,49,51,58,59,62,63,66,67], including targeted therapy [25,50,65], and experimental therapy such as a novel platinum agent [44], tumor-targeting Salmonella typhimurium A1-R [40,46,47,53,55,56,60] and recombinant methioninase (r-ME-Tase) [31,35,42,52,54,55,57,61] in a preclinical model, without the patient suffering from the potential toxicity and morbidity of ineffective drugs. In an era of increasing promise of novel systemic treatment and precision oncology, PDOX models present a unique opportunity to provide sarcoma patients with improved and personalized treatment options. ...
Sarcoma is a rare and recalcitrant malignancy. Although immune and novel targeted therapies have been tested on many cancer types, few sarcoma patients have had durable responses with such therapy. Doxorubicin and cisplatinum are still first line chemotherapy after four decades. Our laboratory has established the patient-derived orthotopic xenograft (PDOX) model using surgical orthotopic implantation (SOI). Many promising results have been obtained using the sarcoma PDOX model for identifying effective approved drugs and experimental therapeutics, as well as combinations of them for individual patients. In this review, we present our laboratory's experience with PDOX models of sarcoma, and the ability of the PDOX models to identify effective approved agents-as well as experimental-therapeutics.
... Another alternative of oncolytic S. typhimurium is the A1-R auxotrophic strain, which is restricted to replicate in tumours. A1-R oncolytic activity has been proved in several cancer models in mice such as prostate (Toneri et al. 2015), breast (Fu, Le and Hoffman 1993), lung , pancreas (Hiroshima et al. 2014), bone (Hayashi et al. 2009), ovary (Matsumoto et al. 2014), gastrointestinal (Miyake et al. 2018), melanoma (Yamamoto et al. 2016), cervical (Hiroshima et al. 2015a) and colorectal cancers (Hoffman 2016). S. typhimurium A1-R is a more specific tumour coloniser and less toxic than the VNP20009 strain in a CT26 colorectal tumor model in syngeneic Balb/c mice (Zhang et al. 2017) or Lewis lung tumor model in nude mice . ...
More than a century ago, independent groups raised the possibility of using bacteria to selectively infect tumors. Such treatment induces an immune reaction that can cause tumor rejection and protect the patient against further recurrences. One of the first holistic approximations to use bacteria in cancer treatment was performed by William Coley, considered the father of immune-therapy, at the end of XIX century. Since then, many groups have used different bacteria to test their antitumor activity in animal models and patients. The basis for this reactivity implies that innate immune responses activated upon bacteria recognition, also react against the tumor. Different publications have addressed several aspects of oncolytic bacteria. In the present review we will focus on revisiting the historical aspects using bacteria as oncolytic agents and how they led to the current clinical trials. In addition, we address the molecules present in oncolytic bacteria that induce specific toxic effects against the tumors as well as the activation of host immune responses in order to trigger antitumor immunity. Finally we discuss future perspectives that could be considered in the different fields implicated in the implementation of this kind of therapy in order to improve the current use of bacteria as oncolytic agents.
... From 2014 to 2018, a total of 17 articles describing the efficacy of S. typhimurium A1-R in PDOX models were identified. All of the 17 studies of human cancer of different histological types were evaluated and the efficacy of S. typhimurium A1-R was compared with the efficacy of chemotherapy (Tables 1 and 2) [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. There were six soft tissue sarcoma (STS) PDOX studies, including rare type tumors [25,27,28,33,37,39], four melanoma PDOX studies [26,29,30,34], three pancreatic cancer PDOX studies [23,24,36], two osteosarcoma PDOX studies [31,35], a gastrointestinal stromal tumor (GIST) PDOX study [32], and a carcinoma of unknown primary (CUP) PDOX study [38]. ...
... All of the 17 studies of human cancer of different histological types were evaluated and the efficacy of S. typhimurium A1-R was compared with the efficacy of chemotherapy (Tables 1 and 2) [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. There were six soft tissue sarcoma (STS) PDOX studies, including rare type tumors [25,27,28,33,37,39], four melanoma PDOX studies [26,29,30,34], three pancreatic cancer PDOX studies [23,24,36], two osteosarcoma PDOX studies [31,35], a gastrointestinal stromal tumor (GIST) PDOX study [32], and a carcinoma of unknown primary (CUP) PDOX study [38]. Ten of the 17 tumors were derived from primary sites [23,24,[26][27][28][29][30]34,36,37], while the remaining seven tumors were recurrent or metastatic [25,[31][32][33]35,38,39]. Two PDOX models from different cancer types were established from the tumors grown in distant lesions [31,35]. ...
... There were six soft tissue sarcoma (STS) PDOX studies, including rare type tumors [25,27,28,33,37,39], four melanoma PDOX studies [26,29,30,34], three pancreatic cancer PDOX studies [23,24,36], two osteosarcoma PDOX studies [31,35], a gastrointestinal stromal tumor (GIST) PDOX study [32], and a carcinoma of unknown primary (CUP) PDOX study [38]. Ten of the 17 tumors were derived from primary sites [23,24,[26][27][28][29][30]34,36,37], while the remaining seven tumors were recurrent or metastatic [25,[31][32][33]35,38,39]. Two PDOX models from different cancer types were established from the tumors grown in distant lesions [31,35]. ...
We developed tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R, a facultative anaerobe that is an auxotroph of leucine and arginine. The tumor-targeting efficacy of S. typhimurium A1-R was demonstrated in vivo and vitro using several malignant cell lines including melanoma, sarcoma, glioma, breast, pancreatic, colon, cervical, prostate, and ovarian cancers. Our laboratory also developed a patient-derived orthotopic xenograft (PDOX) model by implanting patient-derived malignant tumor fragments into orthotopic sites in mice. We reviewed studies of S. typhimurium A1-R against recalcitrant cancers. S. typhimurium A1-R was effective against all PDOX tumor models tested and showed stronger efficacies than chemotherapy or molecular-targeting therapy against some tumors. Furthermore, the synergistic efficacy of S. typhimurium A1-R when combined with chemotherapeutic agents, molecular-targeting agents, or recombinant methioninase was also demonstrated. We suggest potential clinical uses of this S. typhimurium A1-R treatment.
Bacteria have been explored for their potential in fighting against cancer for decades. Due to their outstanding tumor‐targeting capacity and high biocompatibility, live bacteria can serve as microrobots delivering and producing anti‐tumor agents. In addition, live bacteria have intrinsic immune‐activating functions that aid in the generation of anti‐tumor immunity both systemically and locally in the tumor microenvironment. While bacteria‐based cancer therapy is still facing great challenges, progress in this platform combined with nanobiotechnologies has shown promise in terms of safety and effectiveness. Here, basic development strategies of bacteria‐based delivery systems armed with nanotechnologies, virulence attenuation, and genetic manipulation are summarized and the design of a spatiotemporal selectivity is particularly emphasized. In conclusion, the engineered bacteria platform has a high potentiality in the development of novel cancer therapeutics and holds prospects for future investigation and clinical use.
The active role of bacteria in oncogenesis has long been a topic of debate. Although, it was speculated to be a transmissible cause of cancer as early as the 16th-century, yet the idea about the direct involvement of bacteria in cancer development has only been explored in recent decades. More recently, several studies have uncovered the mechanisms behind the carcinogenic potential of bacteria which are inflammation, immune evasion, pro-carcinogenic metabolite production, DNA damage and genomic instability. On the other side, the recent development on the understanding of tumor microenvironment and technological advancements has turned this enemy into an ally. Studies using bacteria for cancer treatment and detection have shown noticeable effects. Therapeutic abilities of bioengineered live bacteria such as high specificity, selective cytotoxicity to cancer cells, responsiveness to external signals and control after ingestion have helped to overcome the challenges faced by conventional cancer therapies and highlighted the bacterial based therapy as an ideal approach for cancer treatment. In this review, we have made an effort to compile substantial evidence to support the multidimensional role of bacteria in cancer. We have discussed the multifaceted role of bacteria in cancer by highlighting the wide impact of bacteria on different cancer types, their mechanisms of actions in inducing carcinogenicity, followed by the diagnostic and therapeutic potential of bacteria in cancers. Moreover, we have also highlighted the existing gaps in the knowledge of the association between bacteria and cancer as well as the limitation and advantage of bacteria-based therapies in cancer. A better understanding of these multidimensional roles of bacteria in cancer can open up the new doorways to develop early detection strategies, prevent cancer, and develop therapeutic tactics to cure this devastating disease.
Traditional methods for cancer therapy, including radiotherapy, chemotherapy, and immunotherapy are characterized by inherent limitations. Bacteria-mediated tumor therapy is becoming a promising approach in cancer treatment due to the ability of obligate or facultative anaerobic microorganisms to penetrate and proliferate in hypoxic regions of tumors. It is widely known that anaerobic bacteria cause the regression of tumors and inhibition of metastasis through a variety of mechanisms, including toxin production, anaerobic lifestyle and synergy with anti-cancer drugs. These features have the potential to be used as a supplement to conventional cancer treatment. To the best of our knowledge, no reports have been published regarding the most common tumor-targeting bacterial agents with special consideration of obligate anaerobes (such as Clostridium sp., Bifidobacterium sp.) and facultative anaerobes (including Salmonella sp., Listeria monocytogenes, Lactobacillus sp., Escherichia coli, Corynebacterium diphteriae and Pseudomonas sp). In this review, we summarize the latest literature on the role of these bacteria in cancer treatment.
Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC 50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF þ VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R þ CAF þ VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential.
Bacterial-mediated cancer therapy (BMCT) has become a hot topic in the area of antitumor treatment. Salmonella has been recommended to specifically colonize and proliferate inside tumors and even inhibit tumor growth. Salmonella typhimurium (S. typhimurium) is one of the most promising mediators, which can be easily manipulated. S. typhimurium has been engineered and designed as cancer-targeting therapeutics, and can be improved by combining with other therapeutic methods, e.g. chemotherapy and radiotherapy, which regulate the tumor microenvironment synergistically. In view of all these strengths, the engineered attenuated strains have significant advantages for tumor diagnosis and treatment. This treatment has also been approved by the FDA for clinical trial. In this review, we summarized the recent progress and research in the field of Salmonella -mediated cancer therapy.
