Oncolytic Probiotics Mediated Checkpoint Inhibition Therapies

Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function. Currently approved checkpoint inhibitors target the molecules CTLA4, PD-1, and PD-L1.

Immune checkpoint inhibitors (CPI) are a promising and increasingly popular approach in treating cancers. Recent years have witnessed the wide application of anti-PD-1, anti-CTLA4, and anti-PD-L1 antibodies in various types of cancer. FDA approvals and ongoing clinical development of checkpoint inhibitors for treatment of various cancers highlight the immense potential of checkpoint inhibitors as anti-cancer therapeutics. Methods of sustained and tumor-targeted delivery of checkpoint inhibitors are likely to improve efficacy while also decreasing toxic side effects. Immune check-point blockade (ICB) uses monoclonal antibodies (MAbs) to block the binding of inhibitory receptors (IRs) to their natural ligands. To create the new anticancer system, the research team engineered probiotic Escherichia coli Nissle 1917 to produce nanobodies—segments of antibodies—that block a molecule on cancer cells called PD-L1 or CTLA-4 on immune cells. These are checkpoint molecules, and blocking them overrides a signal produced by cancer cells to tamp down the immune response. By blocking PD-L1 and CTLA-4, the nanobodies make immune cells better cancer killers.

Gut Microbiome Analysis

Strengths of bacterial delivery systems

• Preferred accumulation and proliferation in tumor tissues
• Ability to penetrate tissues
• Expression of chemotactic receptors for migration to TME
• Can be easily genetically engineered to carry various therapeutics and targeting moieties
• Modifiable promotors that respond to different agents (small molecules, radiation, etc.)
• Ability to stimulate immune system
• Potential for oral delivery

Weaknesses of bacterial delivery systems

• Residual bacterial virulence might be an issue in immunocompromised patients
• Effective colonization and targeting may not be achieved in small metastatic lesions
• Concerns of genetic instability, mutations, and horizontal gene transfers
• Existing immunity against the bacterial vectors may reduce efficacy

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1. Lamichhane, P., Deshmukh, R., Brown, J. A., Jakubski, S., Parajuli, P., Nolan, T., … Lamichhane, N. (2019). Novel Delivery Systems for Checkpoint Inhibitors. Medicines, 6(3), 74.
2. Gurbatri, C. R., Lia, I., Vincent, R., Coker, C., Castro, S., Treuting, P. M., … Danino, T. (2020). Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies. Science Translational Medicine, 12(530)
3. Brunner-Weinzierl, M. C., & Rudd, C. E. (2018). Ctla-4 and pd-1 control of t-cell motility and migration: implications for tumor immunotherapy. Frontiers in Immunology, 9.

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