Lung cancer is the deadliest cancer in the United States and around the world. Many of the currently available therapies have been ineffective, leaving patients with very few options.
A promising new strategy to treat cancer has been bacterial therapy, but while this treatment modality has quickly progressed from laboratory experiments to clinical trials in the last five years, the most effective treatment for certain types of cancers may be in combination with other drugs.
Lung cancer is the deadliest cancer in the United States and around the world. Many of the currently available therapies have been ineffective, leaving patients with very few options.
This new approach was able to rapidly characterize bacterial therapies and successfully integrate them with current targeted therapies for lung cancer.
“We envision a fast and selective expansion of our pipeline to improve treatment efficacy and safety for solid tumors,” said first author Dhruba Deb, an associate research scientist who studies the effect of bacterial toxins on lung cancer in Professor Tal Danino’s lab in Biomedical Engineering, “As someone who has lost loved ones to cancer, I would like to see this strategy move from the bench to bedside in the future.”
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Mechanisms of Bacterial Action in Cancer Treatment
Live strains of Streptococci and Clostridia were the first strains to be used for trials in cancer treatment. A variety of techniques can be used on bacteria in order to achieve tumor therapy [10]. Bacteria belonging to the genus of Pseudomonas, Caulobacter, Listeria, Proteus, Bifidobacteria, and Salmonellae among many others have been shown to have the capability to destroy tumors through different mechanisms.
Some of the mechanisms involve the use of their bacterial toxicity, producing immunotherapic constituents, producing enzymes, producing biofilms, producing bacteriocins, capability to carry out RNA interference as well as prodrug cleavage [11]. These bacterial species have also been tested for their therapeutic effect in cancer in animal models [12, 13]; however, more work has to be done so that the trials can be carried out in humans with different malignancies.
Bacteria as Anticancer Operators through a Triggering Immune Response
Bacteria has been shown to induce an immune response that activates specific types of host immune cells that recognize cancer cells as antigens and destroy them. This includes the activation of T lymphocytes and cytokines [14].
Activation of Cytokines
There are microbes such as Salmonella typhimurium that are able to activate cytokines. They achieve this by activating the pathways that increases the production of cytokine such as IL-1β, TNF-α, and Il-18. The production of these cytokines in abundance results in tumor destruction since interleukins are the ones that contribute more in fighting pathogens [15, 16].
Activation of T Cell Lymphocytes
Escherichia coli (E. coli) have shown to have the capability of producing lymphocytes T cells which are very important in the destruction of tumors [17]. E. coli stimulates and activates the production of CD8+T which has been proved to have the ability to destruct tumors after bacterial infection [17]. E. coli also stimulates the production of CD4+T cells which also helps in the antitumor activity [17]. These T cell lymphocytes also have the ability to eradicate colon cancer and this was confirmed by a trial in severe infected mice which showed cancer reduction upon the administration of T cell lymphocytes [18].
Activation of Tumor Necrosis
Tumor necrosis factor (TN-α) contributes towards the formation of drainage in tumors. The bacterium is able to stimulate the production of tumor necrosis factor, which has been reported with Salmonella enterica serovar Typhimurium [19]. The mechanism in which it works also codes for the production of the neutrophilic granulocytes. The neutrophiles enhance the migration of bacteria to the site of infection, which is the tumor [19]. Studies have revealed that increase in host’s neutrophils decides the victory of bacteria-mediated tumor treatment; hence, the total clearance of recognized tumors is achievable with the expanding estimate of necrosis [19].
reference link :https://www.hindawi.com/journals/emi/2022/8127137/#introduction
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The team used RNA sequencing to discover how cancer cells were responding to bacteria at the cellular and molecular levels. They built a hypothesis on which molecular pathways of cancer cells were helping the cells to be resistant to the bacteria therapy. To test their hypothesis, the researchers blocked these pathways with current cancer drugs and showed that combining the drugs with bacterial toxins is more effective in eliminating lung cancer cells. They validated the combination of bacteria therapy with an AKT-inhibitor as an example in mouse models of lung cancer.
“This new study describes an exciting drug development pipeline that has been previously unexplored in lung cancer—the use of toxins derived from bacteria,” said Upal Basu Roy, executive director of research, LUNGevity Foundation, U.S.. “The preclinical data presented in the manuscript provides a strong rationale for continued research in this area, thereby opening up the possibility of new treatment options for patients diagnosed with this lethal disease.”
Deb plans to expand his strategy to larger studies in preclinical models of difficult-to-treat lung cancers and collaborate with clinicians to make a push for the clinical translation.
More information: Dhruba Deb et al, Design of combination therapy for engineered bacterial therapeutics in non-small cell lung cancer, Scientific Reports (2022). DOI: 10.1038/s41598-022-26105-1
