Bacterial therapy

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Design of engineered live bacterial therapeutics Considerations for the design of engineered live bacterial therapeutics.pdf
Design of engineered live bacterial therapeutics

Bacterial therapy is the therapeutic use of bacteria to treat diseases. Bacterial therapeutics are living medicines, and may be wild type bacteria (often in the form of probiotics) or bacteria that have been genetically engineered to possess therapeutic properties that is injected into a patient. [2] [3] Other examples of living medicines include cellular therapeutics (including immunotherapeutics), activators of anti-tumor immunity, or synergizing with existing tools and approaches. and phage therapeutics, or as delivery vehicles for treatment, diagnosis, or imaging, complementing or synergizing with existing tools and approaches.

Contents

Development

Workflow for developing engineered strains. Strategy for the development of engineered live bacterial therapeutic clinical candidates.pdf
Workflow for developing engineered strains.

Development of bacterial therapeutics is an extremely active research area in the fields of synthetic biology and microbiology. [4] [5] [6] [7] [8] [9] [1] [10] [11] Currently, there is a large focus on: 1) identifying bacteria that naturally produce therapeutic effects (for example, probiotic bacteria), and 2) genetically programming bacteria to produce therapeutic effects. [12] [13] [14]

Design

Optimal strain design often requires a balance between strain suitability for function in the target microenvironment and concerns for feasibility of manufacturing and clinical development. [1]

The development workflow should incorporate technologies for optimizing strain potency, as well as predictive in vitro and in vivo assays, as well quantitative pharmacology models, to maximize translational potential for patient populations. [1]

Applications

Cancer therapy

Schematic of therapeutic bacteria strategies against hypoxic tumors Schematic of therapeutic bacteria strategies against hypoxic tumors.svg
Schematic of therapeutic bacteria strategies against hypoxic tumors
Mechanisms by which bacteria target tumors Mechanisms by which bacteria target tumors.svg
Mechanisms by which bacteria target tumors

There is tremendous interest in using bacteria as a therapy to treat tumors. In particular, tumor-homing bacteria that thrive in hypoxic environments are particularly attractive for this purpose, as they will tend to migrate to, invade (through the leaky vasculature in the tumor microenvironment) and colonize tumors. This property tends to increase their residence time in the tumor, giving them longer to exert their therapeutic effects, in contrast to other bacteria that would be quickly cleared by the immune system. [15] [16] [17] In addition, colonized bacteria can lyze the tumor, activate anti-tumor immune response, can be engineered as a delivery vehicle for anti-cancer therapeutics and may have the potential as contrast agents for cancer imaging. Microbial-based cancer therapy may offer an opportunity to address the issue of global cancer therapy disparity and introduce more suitable cancer immunotherapy approach to low- and middle-income countries. [18]

Mechanism

Genetically engineered probiotics as living medicines to treat intestinal inflammation Probiotic-associated therapeutic curli hybrids (PATCH).pdf
Genetically engineered probiotics as living medicines to treat intestinal inflammation
Bacteria involved in causing and treating cancers Bacteria involved in causing and treating cancers.svg
Bacteria involved in causing and treating cancers

After systemic administration, bacteria localize to the tumor microenvironment. The interactions between bacteria, cancer cells, and the surrounding microenvironment cause various alterations in tumor-infiltrating immune cells, cytokines, and chemokines, which further facilitate tumor regression. ① Bacterial toxins from S. Typhimurium, Listeria, and Clostridium can kill tumor cells directly by inducing apoptosis or autophagy. Toxins delivered via Salmonella can upregulate Connexin 43 (Cx43), leading to bacteria-induced gap junctions between the tumor and dendritic cells (DCs), which allow cross-presentation of tumor antigens to the DCs. ② Upon exposure to tumor antigens and interaction with bacterial components, DCs secrete robust amounts of the proinflammatory cytokine IL-1β, which subsequently activates CD8+ T cells. ③ The antitumor response of the activated CD8+ T cells is further enhanced by bacterial flagellin (a protein subunit of the bacterial flagellum) via TLR5 activation. The perforin and granzyme proteins secreted by activated CD8+ T cells efficiently kill tumor cells in primary and metastatic tumors. ④ Flagellin and TLR5 signaling also decreases the abundance of CD4+ CD25+ regulatory T (Treg) cells, which subsequently improves the antitumor response of the activated CD8+ T cells. ⑤ S. Typhimurium flagellin stimulates NK cells to produce interferon-γ (IFN-γ), an important cytokine for both innate and adaptive immunity. ⑥ Listeria-infected MDSCs shift into an immune-stimulating phenotype characterized by increased IL-12 production, which further enhances the CD8+ T and NK cell responses. ⑦ Both S. Typhimurium and Clostridium infection can stimulate significant neutrophil accumulation. Elevated secretion of TNF-α and TNF-related apoptosis-inducing ligand (TRAIL) by neutrophils enhances the immune response and kills tumor cells by inducing apoptosis. ⑧ The macrophage inflammasome is activated through contact with bacterial components (LPS and flagellin) and Salmonella-damaged cancer cells, leading to elevated secretion of IL-1β and TNF-α into the tumor microenvironment. NK cell: natural killer cell. Treg cell: regulatory T cell. MDSCs: myeloid-derived suppressor cells. P2X7 receptor: purinoceptor 7-extracellular ATP receptor. LPS: lipopolysaccharide [15]

Clostridioides difficile infection therapy

Alterations in the gut microbiome are thought to be associated with C. difficile infection and recurrence. [19] Therapies include probiotics and fecal microbiota transplantation.

Microbiome engineering

There is considerable interest in using bacterial therapeutics to alter human gastrointestinal microbiota to help diseases like small intestinal bacterial overgrowth, gut dysbiosis associated with the pathogenesis of food allergy, [20] and other forms of dysbiosis.


See also

Related Research Articles

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Tumor necrosis factor</span> Immune system messenger protein which induces inflammation

Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors on other cells. It is a member of the tumor necrosis factor superfamily, a family of transmembrane proteins that are cytokines, chemical messengers of the immune system. Excessive production of TNF plays a critical role in several inflammatory diseases, and TNF-blocking drugs are often employed to treat these diseases.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Lymphotoxin is a member of the tumor necrosis factor (TNF) superfamily of cytokines, whose members are responsible for regulating the growth and function of lymphocytes and are expressed by a wide variety of cells in the body.

<span class="mw-page-title-main">TNFSF9</span> Protein-coding gene in humans

Tumor necrosis factor ligand superfamily member 9 also known as 4-1BB ligand or 4-1BBL or CD137L is a protein that in humans is encoded by the TNFSF9 gene.

<span class="mw-page-title-main">CD137</span> Protein found in humans

CD137, a member of the tumor necrosis factor (TNF) receptor family, is a type 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule, and as a potential target in cancer immunotherapy.

<span class="mw-page-title-main">Toll-like receptor 5</span> Protein found in humans

Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has been shown to be involved in the onset of many diseases, including Inflammatory bowel disease due to the high expression of TLR in intestinal lamina propria dendritic cells. Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis, osteoclastogenesis, and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.

<span class="mw-page-title-main">Programmed cell death protein 1</span> Mammalian protein found in humans

Programmed cell death protein 1(PD-1),. PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

<span class="mw-page-title-main">BTLA</span> Protein-coding gene in the species Homo sapiens

B- and T-lymphocyte attenuator or BTLA is a protein that belongs to the CD28 immunoglobulin superfamily (IgSF) which is encoded by the BTLA gene located on the 3rd human chromosome. BTLA was first discovered in 2003 as an inhibitor of Th1 expansion and it became the 3rd member of the CD28 IgSF. However, its discovered ligand herpes virus entry mediator or HVEM belongs to the tumor necrosis factor receptor superfamily (TNFRSF). This finding was surprising because until the discovery of HVEM it was believed that receptors and ligands always belong to the same family.

A macrophage-activating factor (MAF) is a lymphokine or other receptor based signal that primes macrophages towards cytotoxicity to tumors, cytokine secretion, or clearance of pathogens. Similar molecules may cause development of an inhibitory, regulatory phenotype. A MAF can also alter the ability of macrophages to present MHC I antigen, participate in Th responses, and/or affect other immune responses.

Urelumab is a fully human, non‐ligand binding, CD137 agonist immunoglobulin‐γ 4 (IgG4) monoclonal antibody. It was developed utilizing Medarex's UltiMAb(R) technology by Bristol-Myers Squibb for the treatment of cancer and solid tumors. Urelumab promotes anti-tumor immunity, or an immune response against tumor cells, via CD137 activation. The application of Urelumab has been limited because it can cause severe liver toxicity.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage.

<span class="mw-page-title-main">Immune checkpoint</span> Regulators of the immune system

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.

Clostridium novyi-NT is an attenuated strain of Clostridium novyi that is under investigation as a cancer treatment. It is one of several pathogenic species of Clostridium bacteria that have been examined for this purpose. The modification eliminated the secretion of α-toxin.

The dendritic cell-based cancer vaccine is an innovation in therapeutic strategy for cancer patients.

<span class="mw-page-title-main">Living medicine</span>

A living medicine is a type of biologic that consists of a living organism that is used to treat a disease. This usually takes the form of a cell or a virus that has been genetically engineered to possess therapeutic properties that is injected into a patient. Perhaps the oldest use of a living medicine is the use of leeches for bloodletting, though living medicines have advanced tremendously since that time.

Tumor-homing bacteria are facultative or obligate anaerobic bacteria that are able to target cancerous cells in the body, suppress tumor growth and survive in the body for a long time even after the infection. When this type of bacteria is administered into the body, it migrates to the cancerous tissues and starts to grow, and then deploys distinct mechanisms to destroy solid tumors. Each bacteria species uses a different process to eliminate the tumor. Some common tumor homing bacteria include Salmonella, Clostridium, Bifidobacterium, Listeria, and Streptococcus. The earliest research of this type of bacteria was highlighted in 1813 when scientists began observing that patients that had gas gangrene, an infection caused by the bacteria Clostridium, were able to have tumor regressions.

Laurence Zitvogel is a French physician-scientist specializing in oncology and immunology. Zitvogel is a clinical oncologist, a researcher in the Laboratory of Tumor Immunology and Immunotherapy, and a professor at Paris-Saclay University. She has studied the correlation between the immune system and the success of cancer treatments for over 30 years. Her primary research experience lies in exosomes, studying the biological impact of structural abnormalities on malignant neoplasms, and anti-tumor therapy. Through her work as a professor and researcher, Zitvogel discovered that chemotherapy could delay the growth of tumors in mouse models. Her team reported the first anticancer probiotic, Enterococcus hirae. As of 2020, she is researching an effective and inexpensive diagnostic test to predict dysbiosis and is investigating the promising lead on the role of gut microbiotes in anti-tumour immunotherapy.

RNA therapeutics are a new class of medications based on ribonucleic acid (RNA). Research has been working on clinical use since the 1990s, with significant success in cancer therapy in the early 2010s. In 2020 and 2021, mRNA vaccines have been developed globally for use in combating the coronavirus disease. The Pfizer–BioNTech COVID-19 vaccine was the first mRNA vaccine approved by a medicines regulator, followed by the Moderna COVID-19 vaccine, and others.

References

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  2. ↑ Sample I (16 January 2019). "'Living medicine' helps make toxic ammonia breakthrough". The Guardian.
  3. ↑ Whitaker W, Shepherd E, DeLoache WC, Russ ZN (2019). Engineering Living Medicines for Chronic Diseases. Microbiome Engineering.
  4. ↑ Weber W, Fussenegger M (November 2011). "Emerging biomedical applications of synthetic biology". Nature Reviews. Genetics. 13 (1): 21–35. doi:10.1038/nrg3094. PMC   7097403 . PMID   22124480.
  5. ↑ Fischbach MA, Bluestone JA, Lim WA (April 2013). "Cell-based therapeutics: the next pillar of medicine". Science Translational Medicine. 5 (179): 179ps7. doi:10.1126/scitranslmed.3005568. PMC   3772767 . PMID   23552369.
  6. ↑ Kitada T, DiAndreth B, Teague B, Weiss R (February 2018). "Programming gene and engineered-cell therapies with synthetic biology". Science. 359 (6376): eaad1067. doi:10.1126/science.aad1067. PMC   7643872 . PMID   29439214.
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  9. ↑ Kurtz CB, Millet YA, Puurunen MK, Perreault M, Charbonneau MR, Isabella VM, et al. (January 2019). "An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans". Science Translational Medicine. 11 (475): eaau7975. doi: 10.1126/scitranslmed.aau7975 . PMID   30651324. S2CID   58031579.
  10. ↑ "Gene Circuits Empower Next-Generation Cell and Gene Therapies". GEN - Genetic Engineering and Biotechnology News. 1 February 2020. Retrieved 5 April 2020.
  11. ↑ Gurbatri, Candice R.; Arpaia, Nicholas; Danino, Tal (25 November 2022). "Engineering bacteria as interactive cancer therapies". Science. 378 (6622): 858–864. Bibcode:2022Sci...378..858G. doi:10.1126/science.add9667. PMC   10584033 . PMID   36423303. S2CID   253839557.
  12. ↑ Triassi A (2 April 2019). "Why now is the time for programmable living medicines: insights from Jim Collins, Aoife Brennan, and Jason Kelly". SynBioBeta. Archived from the original on 17 April 2019.
  13. ↑ Costa K (20 February 2019). "Living medicines: Ginkgo's machine to disrupt the pharma industry". SynBioBeta. Archived from the original on 15 December 2019.
  14. ↑ Sieow BF, Wun KS, Yong WP, Hwang IY, Chang MW (May 2021). "Tweak to Treat: Reprograming Bacteria for Cancer Treatment". Trends in Cancer. 7 (5): 447–464. doi: 10.1016/j.trecan.2020.11.004 . PMID   33303401.
  15. 1 2 Duong MT, Qin Y, You SH, Min JJ (December 2019). "Bacteria-cancer interactions: bacteria-based cancer therapy". Experimental & Molecular Medicine. 51 (12): 1–15. doi:10.1038/s12276-019-0297-0. PMC   6906302 . PMID   31827064.
  16. ↑ Sedighi M, Zahedi Bialvaei A, Hamblin MR, Ohadi E, Asadi A, Halajzadeh M, et al. (June 2019). "Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities". Cancer Medicine. 8 (6): 3167–3181. doi:10.1002/cam4.2148. PMC   6558487 . PMID   30950210.
  17. ↑ Song S, Vuai MS, Zhong M (December 2018). "The role of bacteria in cancer therapy - enemies in the past, but allies at present". Infectious Agents and Cancer. 13 (1): 9. doi: 10.1186/s13027-018-0180-y . PMC   5856380 . PMID   29568324.
  18. ↑ Salicrup LA, Ossandon M, Prickril B, Rasooly A (June 2020). "Bugs as Drugs, potential self-regenerated innovative cancer therapeutics approach for global health". Journal of Global Health. 10 (1): 010311. doi:10.7189/jogh.10.010311. PMC   7100862 . PMID   32257138.
  19. ↑ Na, Xi; Kelly, Ciaran (November 2011). "Probiotics in Clostridium difficile Infection". Journal of Clinical Gastroenterology. 45 (Suppl): S154–S158. doi:10.1097/MCG.0b013e31822ec787. ISSN   0192-0790. PMC   5322762 . PMID   21992956.
  20. ↑ Rachid R, Stephen-Victor E, Chatila TA (March 2021). "The microbial origins of food allergy". The Journal of Allergy and Clinical Immunology. 147 (3): 808–813. doi:10.1016/j.jaci.2020.12.624. PMC   8096615 . PMID   33347905.
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