Live Biotherapeutics: Targeting The Microbiome For The Cancer Treatment

The quest to create microbial products that can influence cancer outcomes has been re kindled by the mounting evidence of the role that microbiota plays in human health and illness.

Fecal microbiota transplants (FMT), probiotics, naturally colonized bacteria (found surrounding stressed bodily tissues, such as solid tumors), and synthetic bacteria are all considered live biotherapeutics. These categories of live biotherapeutics are being used to treat cancer and are being researched to mitigate side effects through a variety of mechanisms, including immune cell activation, treatment resistance overcome, tumor specificity and killing, inflammation dampening, and therapeutic payload delivery.[1,2,3] 

Conventional cancer treatments, including radiation and chemotherapy, can cause systemic side effects, and surgery may not be able to fully remove malignancies, which might result in recurrence. While immunotherapies like CAR-T cell therapy for cancers have improved patient outcomes and therapeutic alternatives, there are still obstacles associated with these treatments, as many of them have a non-localized therapeutic effect and are ineffective against immune-blocking tumors and eliminating the solid tumors. Through the release of cytokines, short-hairpin RNA (shRNA), and tumor associated antigens (TAAs) are certain ways been developed as bacterial therapies that have been designed to stimulate the host immune system via adaptive or innate immune system. Numerous of such treatments focus on both immune system together have the ability to reverse immunosuppression. The next generation of bacterially designed therapeutics has the ability to induce immunological responses in malignancies that evade the immune system and deposit medications directly into tumors. Certain facultative anaerobes, such Salmonella and Listeria are known to selectively target solid tumors and their metastases. Other examples of oncolytic bacteria include as Streptococcus, Serratia species, and Mycobacterium bovis (BCG). Intravesical TICE ® BCG got FDA approval & has been utilized as prophylactic treatment for recurrent tumors in patients with bladder cancer in situ (CIS) and as a treatment for only Stage TaT1 papillary tumors of the bladder that are at high risk of recurrence after careful SWOG 8795 study and the Nijmegen study. ^[1] 

Biomedical application of engineered bacteria 

Even though bacteria cannot completely eradicate tumors, they can induce antitumor immunity by expanding within the immune-privileged tumor microenvironment (TME) and decreasing immunosuppression. As a result, the possibility of producing bacteria that carry therapeutic payloads—that is, drugs—may hold great promise in the treatment of cancer. In bacteria-based cancer immunotherapy (BCiT) genetic engineering is used to induce precise and effective antitumor responses. A potent antitumor immune response was elicited by introducing a gene circuit encoding an orthogonal heat switch into the E. coli Nissle 1917 (EcN) strain, which expressed either melanin or tumor necrosis factor-α (TNF-α). In order to create EcN, a temperature-activated genetic switch was incorporated. This switch caused immune checkpoint inhibitors and other therapeutic medicines to be expressed in response to hypothermia (externally triggered) brought on by a brief focused ultrasound treatment (FUS). It is possible to engineer the genetic circuit so that, in response to internal stimuli unique to the tumor, such as a certain pH, oxygen concentration, or glucose gradient in the TME, the bacteria precisely manufacture therapeutic chemicals.  QS-responsive compounds, such as acyl-homoserine lactone (AHL), were introduced into E. coli and made to express themselves. These molecules caused bacterial lysis and the subsequent release of therapeutic payload when the bacterial population density within the TME reached a certain threshold. A mixture of gene circuits can be created using a synthetic logic circuit system to react to various input signals and stop leaky expression that results from a single gene circuit. E. coli has been modified to carry the QS-based AND logic gate, which senses an extra input signal, such as IPTG or anhydrotetracycline (aTc), in addition to AHL, in order to regulate gene expression.^[2,4] 

Live bacteria as potent immune adjuvants 

In malignancies, live bacteria function as potent immune adjuvants, drawing in and activating innate immune cells such neutrophils, macrophages, and monocytes. Inflammatory cytokines like interleukin-1β (IL-1β), TNF-α, and interferon-γ (IFN-γ) are produced by these activated immune cells. In 22 patients with metastatic gastrointestinal cancer, a phase I clinical trial found that oral treatment of Salmonella expressing human IL-2, a powerful immunostimulatory cytokine, markedly boosted the number of circulating natural killer (NK) and NKT cells.^[3]

Preclinical research is no longer the only application for BCiT with live microorganisms. For high-risk, non-muscle-invasive bladder cancer, Bacillus Calmette-Guérin (BCG), a live attenuated Mycobacterium tuberculosis vaccine, has proven to be a successful treatment. Over 50 completed clinical trials using live bacteria, including Salmonella (n = 13), Listeria (n = 32), Clostridium (n = 4), Bifidobacterium (n = 2), and Yersinia (n = 1), for the treatment of various cancers, are listed on the National Institutes of Health's website, clinicaltrials.gov. FMT is now authorized for the treatment of Clostridium difficile infections that do not respond to antibiotics. In order to improve treatment outcomes or lessen unpleasant effects caused by treatment, FMT is currently being explored in cancer patients. The gut microbiota has the ability to influence cancer therapies. Necessary clinical trials in patients with hematologic cancers (NCT04935684, NCT03678493) and solid tumors (NCT05502913, NCT04264975, NCT04577729) may soon offer fresh information regarding the application of fecal microbiota transplantation in cancer treatment.^[2,3] 

In conclusion, live biotherapeutics, such as fecal transplants and modified bacteria, are becoming more and more promising as cancer therapy techniques by taking use of the gut microbiome's impact on health. By specifically targeting tumors, boosting the immune system, and administering medication, these therapies go above and beyond standard techniques. While continuing research investigates genetically altered strains to precisely deliver immune-boosting chemicals or medications based on tumor circumstances, initial studies with bacteria like BCG for bladder cancer show promise. Additionally, fecal transplants are being studied as a potential way to reduce side effects and enhance treatment success. With its more focused and potentially revolutionary approach, this new method has the potential to completely change the way cancer is treated. At research level, combining the microbial and host-centric perspectives on cancer could lead to better patient outcomes and a more complex understanding of the evolution of disease, host, and microbes. 

References: 

1. Anne J Gonzales-Luna, Travis J Carlson, Kevin W Garey, Review Article: Safety of Live Biotherapeutic Products Used for the Prevention of Clostridioides difficile Infection Recurrence, Clinical Infectious Diseases, Volume 77, Issue Supplement_6, 1 December 2023, Pages S487–S496, https://doi.org/10.1093/cid/ciad642.

2. Brevi A, Zarrinpar A. Live Biotherapeutic Products as Cancer Treatments. Cancer Res. 2023 Jun 15;83(12):1929-1932. doi: 10.1158/0008-5472.CAN-22-2626. PMID: 37317784; PMCID: PMC10275495.

3. Nguyen, DH., Chong, A., Hong, Y. et al. Bioengineering of bacteria for cancer immunotherapy. Nat Commun 14, 3553 (2023). https://doi.org/10.1038/s41467-023-39224-8.

4. Shong J, Collins CH. Quorum sensing-modulated AND-gate promoters control gene expression in response to a combination of endogenous and exogenous signals. ACS Synth Biol. 2014 Apr 18;3(4):238-46. doi: 10.1021/sb4000965. Epub 2013 Nov 11. PMID: 24175658.

About the Author:

Shruti Talashi

Ms.  Shruti  Talashi  boasts a dual mastery of lab research and writing.  Her doctoral study outcome as M.Phil in biomedical science while studying  breast cancer and an extraordinary masters degrees dissertation work on  exploring role of Gal-lectin in cancer metastasis fuels her extensive  research interests. She has gained few publication in journals. Bridging the  science-public gap is her passion, aided by expertise in diverse techniques.  From oncology to antibiotic/drugs production, she's led and managed complex  projects, even clinical trials. Now, as a freelance Content Coordinator for  Sinoexpo Pharmasource.com, her industry knowledge shines through valuable  insights on cutting-edge topics like GMP, QbD, and biofoundry.