Programmable bacteria induce durable tumor regression and systemic antitumor immunity

Chowdhury, Sreyan; Hinchliffe, Taylor E.; Castro, Samuel; Coker, Courtney; Arpaia, Nicholas; Danino, Tal

doi:10.1101/561159

Cited by 51 publications

(57 citation statements)

References 29 publications

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“…Myriad strategies employing nanoparticles and even live bacteria as drug delivery vehicles have been proposed for the specific killing of cancerous cells [49][50][51][52] . We suggest that SSHELs provide several unique benefits and that they may be used as an additional strategy for this purpose and may be modified easily to suit different needs.…”

Section: Discussionmentioning

confidence: 99%

Cell-specific cargo delivery using synthetic bacterial spores

Kong

Updegrove

Constantino

et al. 2020

Preprint

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SSHELs are synthetic bacterial spore-like particles wherein the spore's cell surface is partially reconstituted around 1 µm-diameter silica beads coated with a lipid bilayer. Via a unique cysteine engineered in one of the surface proteins, the surface of SSHELs may be covalently decorated with molecules of interest. Here, we modified SSHELs with an affibody directed against HER2, a cell surface protein overexpressed in some breast and ovarian cancer cells, and loaded them with the chemotherapeutic agent doxorubicin. Drug-loaded SSHELs reduced tumor growth with lower toxicity in a mouse tumorxenograft model compared to free drug by specifically binding to HER2-positive cancer cells. We show that SSHELs bound to target cells are taken up and trafficked to acidic compartments, whereupon the cargo is released in a pH-dependent manner. Finally, we demonstrate that SHELLs can clear small tumor lesions in a complex tumor microenvironment in a zebrafish model of brain metastasis. We propose that SSHELs represent a versatile strategy for targeted drug delivery. AUTHOR CONTRIBUTIONS

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Section: Discussionmentioning

confidence: 99%

Cell-specific cargo delivery using synthetic bacterial spores

Kong

Updegrove

Constantino

et al. 2020

Preprint

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“…Several groups are taking the approach to BCT to engineer the bacteria to deliver drugs or other compounds that can further promote tumor death or immune clearance (19,20,(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

“…Effective treatment with STm has been observed in adaptive immune-deficient (nude) mouse models (8,18), suggesting that T cell responses may not be essential for anti-tumor effects. In some studies that have assessed immune infiltrates, only STm or E. coli that were engineered to deliver an immunestimulatory product elicited a significant immune response (19,20). Other studies have shown induction of an immune response, such as induction of IL-1b and TNF-a when delivered i.v.…”

Section: Introductionmentioning

confidence: 99%

AttenuatedSalmonellatyphimurium cancer therapy has direct effects on the tumor epithelium in colorectal cancer

Maslowski

Takahashi

Nakanishi

et al. 2019

Preprint

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One Sentence Summary:Attenuated Salmonella enterica serovar Typhimurium can home to gastrointestinal tumors and directly affect the tumor epithelium, inducing transcriptional and metabolic changes that lead to reduced tumor burden in mice. 2 Abstract: Bacterial cancer therapy (BCT) shows great promise for treatment of solid tumors, yet basic mechanisms of bacterial-induced tumor suppression remain undefined. The intestinal epithelium is the natural route of infection for Salmonella and thus harbors innate immune defenses which protect against infection. Attenuated strains of Salmonella enterica serovar Typhimurium (STm) have commonly been used in mouse models of BCT, largely with the use of xenograft and orthotopic transplant cancer models. We aimed to better understand the tumor epithelium-targeted mechanisms of BCT by using mouse models of intestinal tumorigenesis and tumor organoid cultures to assess the effectiveness and mechanisms of treatment with aromatase A-deficient STm (STm ∆aroA ). STm ∆aroA delivered by oral gavage could significantly reduce tumor burden and tumor load in both a colitis-associated colon cancer model (CAC) and in a spontaneous intestinal cancer model, Apc min/+ mice. STm ∆aroA colonization of tumors caused alterations in transcription of mRNAs associated with epithelial-mesenchymal transition as well as metabolic and cell cycle-related transcripts. Metabolomic analysis of tumors demonstrated alteration in the metabolic environment of STm ∆aroA -treated tumors, suggesting STm ∆aroA imposes metabolic competition on the tumor.Use of tumor organoid cultures in vitro demonstrated that STm ∆aroA can directly affect the tumor epithelium with alterations in transcripts and metabolites similar to in vivo-treated tumors. Thereby, we demonstrate that bacterial cancer therapy is efficacious in autochthonous intestinal cancer models, that BCT imposes metabolic competition, and that BCT has direct effects on the tumor epithelium, which have not previously been appreciated.

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“…For example, one application of interest for SimCells highlighted in this study is bacterial cancer therapy (9). As it is known that some bacteria preferentially associate with tumors (10), synthetic biology tools and concepts can be used to further engineer bacteria to sense, target, and deliver anticancer compounds locally to tumors (11)(12)(13)(14). SimCells offer an additional advantage as a therapeutic agent as they cannot replicate due to the lack of chromosomal DNA.…”

mentioning

confidence: 99%

Chromosome-free bacterial cells are safe and programmable platforms for synthetic biology

Fan

Davison

Habgood

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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A type of chromosome-free cell called SimCells (simple cells) has been generated fromEscherichia coli,Pseudomonas putida, andRalstonia eutropha.The removal of the native chromosomes of these bacteria was achieved by double-stranded breaks made by heterologous I-CeuI endonuclease and the degradation activity of endogenous nucleases. We have shown that the cellular machinery remained functional in these chromosome-free SimCells and was able to process various genetic circuits. This includes the glycolysis pathway (composed of 10 genes) and inducible genetic circuits. It was found that the glycolysis pathway significantly extended longevity of SimCells due to its ability to regenerate ATP and NADH/NADPH. The SimCells were able to continuously express synthetic genetic circuits for 10 d after chromosome removal. As a proof of principle, we demonstrated that SimCells can be used as a safe agent (as they cannot replicate) for bacterial therapy. SimCells were used to synthesize catechol (a potent anticancer drug) from salicylic acid to inhibit lung, brain, and soft-tissue cancer cells. SimCells represent a simplified synthetic biology chassis that can be programmed to manufacture and deliver products safely without interference from the host genome.

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Programmable bacteria induce durable tumor regression and systemic antitumor immunity

Cited by 51 publications

References 29 publications

Cell-specific cargo delivery using synthetic bacterial spores

Cell-specific cargo delivery using synthetic bacterial spores

AttenuatedSalmonellatyphimurium cancer therapy has direct effects on the tumor epithelium in colorectal cancer

Chromosome-free bacterial cells are safe and programmable platforms for synthetic biology

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