Over a hundred years ago William B Coley, the “Father of Immunotherapy”, discovered that injection of bacteria or bacterial toxins into tumors could cause those tumors to shrink. The introduction of bacteria had the side-effect of stimulating the immune system to attack the tumor. The field of cancer immunotherapy research—which today includes many different approaches for generating anti-tumor immune responses—originated with these early experiments.
Use of bacteria is one way to stimulate the immune system to attack cancer cells, others include use of cytokines, immune checkpoint blockades and vaccines. This Nature animation provides a simple overview of these methods.
Caspase-Glo papers and microbial cancer immunotherapy research
Cell health assays are used in many immunotherapy research studies to assess if, when, and how target tumor cells die. Two recent papers using the Caspase-Glo Assay show how old ideas such as the use of microbes for cancer immunotherapy are being re-examined and used together with newer ideas in the search for more effective cancer treatments. In these studies, the Caspase-Glo Assay was used together with other assays to confirm that targeted tumor cells die by apoptosis.
Tissue-targeting bacteria boost immune checkpoint effectiveness in prostate tumors.
Immune checkpoint inhibitors have been in the news a lot recently, due to promising results with certain cancers. However, not all tumors are good candidates for immune checkpoint inhibition. Success is dependent on expression of the appropriate immune checkpoint on the tumor cells and on the number of tumor-infiltrating lymphocytes present. Tumors with low numbers of infiltrating lymphocytes, low expression of the immune checkpoint, and with low rates of mutagenesis are typically resistant to treatment.
Prostate cancer is one example of a cancer that is not amenable to immune checkpoint therapy. These “immunologically cold” tumors express the immune checkpoint PD-L1, but have low mutation rates and few infiltrating T cells. In an April 2018 Nature Communications paper, authors Anker et al investigated whether localized bacterial infection could be used to help stimulate an immune response and render prostate tumors susceptible to immune checkpoint inhibitors. They showed that an E.coli strain (CP-1) isolated from a prostate infection colonized prostate tumors and enhanced immune checkpoint inhibition.
In a mouse model, treatment with these bacteria along with anti-PD-1 immunotherapy increased immunogenic cell death, T cell cytotoxicity, and tumor infiltration by activated T cells. The bacteria persisted locally, but did not spread and cause systemic infection problems. The authors discuss the potential advantages of tissue-specific bacterial treatment as a way of targeting delivery of therapy, as opposed to more non-specific therapies like chemotherapy, T-cell therapies and radiation. The caveat is of course the need for some attenuation/certainty of containment of the bacteria to ensure that they persist locally, but do not spread and cause infection problems.
More broadly, this study demonstrates how select tissue-specific microbes, as are commonly isolated colonizing the breast, pharynx, intestines, bladder, female genital tract, and additional tissues throughout the body, can be screened and evaluated to uncover future CP1-like bacteria to potentiate immunotherapies in other recalcitrant cancers. (Anker et al., 2018 Nat. Comm. 9, 1591)
Tissue-targeted viruses for bladder cancer
In a similar vein, another recent paper using Caspase-Glo investigated the effectiveness of an engineered virus in conjunction with chemotherapy for killing bladder cancer cell lines. The idea of using viruses to target and kill cancer cells has been around for about as long as its bacterial counterpart, but modern molecular approaches are bringing the idea to fruition (see this article for a summary).
Oncolytic viruses specifically target tumor cells. In the June 2018 issue of Molecular Therapy Oncology, authors Annels et al report on use of such a virus for potential treatment of bladder cancer. These authors tested the effects of an engineered oncolytic common cold-type virus (Coxsackie virus -CVA21) on bladder cancer cells in culture and in a mouse model. They showed that surface expression of the viral receptor could be enhanced (and viral anti-tumor activity enhanced) by treatment with the chemotherapeutic agent mitomycin C. Apoptosis was induced in the bladder cancer cell lines infected with the virus and was enhanced by mitomycin c treatment as determined by an Annexin V binding assay and the Caspase-Glo 3/7 Assay. Mitomycin c treatment alone did not induce apoptosis.
The authors cite many other studies investigating viruses and bacteria as cancer immunotherapies.
It takes a multitude
It seems that daily we discover more about the interdependence between bacteria, viruses and ourselves. I have written other blogs about how microbiome studies are uncovering ways in which specific bacteria can influence response to immunotherapy—some bacterial colonists being required for effectiveness. The two papers I have highlighted here are examples from another whole body of work that may allow bacteria or viruses to be used as treatments for disease, either by stimulating an immune response (like in the old days, but in a much more controlled way) or by specifically targeting and killing cancer cells selectively.
We used to think of microorganisms only as pathogens to be eliminated, or harmless colonizers to be tolerated. These studies suggest that in the future intentional infection with microbes designed to home in on and eliminate diseased cells could be a very real possibility.
More information about Caspase-Glo Assays.
- McCarthy E.F. (2006) The Toxins of William B. Coley and the Treatment of Bone and Soft-Tissue Sarcomas Iowa Orthop J. 26, 154–158.
- Anker, J.F. et al. (2018) Multi-faceted immunomodulatory and tissue-tropic clinical bacterial isolate potentiates prostate cancer immunotherapy. Nature Communications 9, Article number: 1591. doi:10.1038/s41467-018-03900-x
- Annels, N.C., et al. (2018) Oncolytic immunotherapy for Bladder Cancer using Cocksackie A21 Virus. Mol. Ther. Oncol. 9, 1–12.
- Ribas, A. et al. (2017) Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell 170(6), 1109-1119. e10
- Haanen, J.B.A.G (2017) Converting Cold into Hot Tumors by Combining Immunotherapies. Cell 170(6), 1055-1056. doi: 10.1016/j.cell.2017.08.031.