The interaction between cancer and bacteria is not new.
As early as 1868, Busch began infecting sarcoma patients with erysipelas. This experiment was a semi-success in sofar as the reduction of the tumors was quickly followed by a reappearance of the cancer (1). In 1891, Coley pursued Busch's work and injected a throat cancer patient with Streptococcus erysipelas cultures: this time, the patient returned to a healthy condition for eight years. Supported by the experiences of Pasteur, Koch and von Behring, and through iterative experimentation, Coley eventually developed a safer mixture of heat-killed Streptococcus and other bacterial toxins, including those coming from Seratia marcescens, Staphylococcus spp and Escherichia coli. Over the next forty years, Coley injected more than 1,000 cancer patients with this therapeutic. This product became known as Coley's Toxins, and immunotherapy was born.
It was only with the advances of radiotherapy and chemotherapy, that Coley toxins were gradually discarded, despite their promises.
But the bacteria hadn't said their last word.
1. The comeback of Coley’s Toxins in cancer treatment
In 1999, Charlie Starnes, a leading researcher at Amgen said, I quote, "what Coley was doing for sarcoma patients at the time was more effective than what we are doing for sarcoma patients today" and added that Coley's toxin would prove to be 38% more effective than today's most modern therapy.
In 2005, Donald H. MacAdam, despite limited financial resources, decided to reignite the Coley fluid and founded MBVax.
Since then, promising results for various tumour entities have been obtained. Coley toxin-stimulated leukocytes from healthy donors were effectively activated and responded with the upregulation of TLR 2, 5 and 9. Similarly, CD25 expression was significantly and durably induced in these short-lived mixed leukocyte cultures, suggesting Tγδ cell stimulation. In addition, secretion of Th1 and other pro-inflammatory cytokines (e.g. IFN-γ, IL12 and TNF-a) by immune cells belonging to both the innate and adaptive arms have been demonstrated (3).
But with the danger linked to bacteria injection and without formal approval from health regulatory bodies, the clinical use of bacteria as therapeutic agents for cancer went undeveloped. And in Canada, the adventure resulted in the complete cessation of work by MBVax after a few years.
Looking back, while Pasteur was interested in pathogenic bacteria, one of his students, Elie Metchnikov, decided a few years later to study the properties of the bacteria present in our gut or microbiota. When the injection of bacteria began to show convincing results, some researchers asked in parallel if the answer wasn't already in us…
2. Gut microbiote & cancer immunotherapy
In 2017, a study conducted by Laurence Zitvogel, scientific director of the Gustave Roussy Cancer Centre in France, showed that patients who had recently taken antibiotics - for urinary tract infections - had lower survival rates than those who did not. After analyzing the participants' microbiotes, the researchers found that a bacterium called Akkermansia muciniphila was linked to strong clinical outcomes (4).
At the same time, at the MD Anderson Cancer Center, a study isolated two bacteria that help support the PD-1 immunotherapy response in metastatic melanoma. Researchers collected oral, intestinal and fecal microbiome samples - as well as tumor biopsies - before and after therapy. Once treatment was complete, they divided patients into "responders" and "non-responders" and developed a genetic profile of each microbiome (5).
"What we found was impressive: there were major differences in both the diversity and composition of the intestinal microbiome in both responders and non-responders", said Dr Jennifer Wargo. Successful responders had greater bacterial diversity in their gut, while those whose tumours didn't shrink much had fewer varieties of microbes.
In addition, immunotherapy responders had a much higher density of killer T cells - which are largely responsible for the attack of cancer. The researchers found that the presence of the bacteria belonging to genus Faecalibacterium and Clostridium seemed to explain the difference in T-cell density.
However, despite the hard work of physicians and investigators, very few candidates have actually been investigated in human clinical trials and most of these clinical studies have so far failed to demonstrate the definitive effect of immunotherapy via bacterial preparation.
3. An unexpected Trojan horse?
Many articles deal with the gut-linked microbiome, but few people know that several microbiomes are present in the body, especially the skin microbiome.
Recently a new article goes even further.
Bacteria reside inside tumour cells and this intratumor bacterial population differs depending on the variety of cancer. Yes, you read me correctly. Tumors have their own microbiome.
The team of Dr. Nejman announced on May 2020 that they found that each tumor type has a distinct microbiome composition and that breast tumors had a richer and more diverse microbiome than all other tumor types tested. An average of 16.4 bacterial species were detected in any single breast tumor sample, whereas the average was less than 9 in all other tumor types. Overall, these results show that live bacteria from three main phyla—Proteobacteria, Firmicutes, and Actinobacteria — can be found in breast tumors (6).
But some questions remain unanswered.
Do intratumor bacteria play a causal role in the development of cancer?
Does bacteria presence reflect the infections of established tumors?
If we suggest that manipulation of the tumor microbiome may also affect tumor immunity and the response to immune therapy, we can now imagine potentially targeting intracellular bacteria residing in tumours as new and non-toxic immunotherapy.
All that's left is to find the remote control to activate these little robots…
REFERENCES
(1) Busch W. Aus der Sitzung der medicinischen Section vom 13 November 1867. Berlin Klin Wochenschr. 1868;5:137. (Ger)
(2) Coley WB. Late results of the treatment of inoperable sarcoma by the mixed toxins of Erysipelas and Bacillus prodigosus. Am J Med Sci. 1906;131:375–430.
(3) Maletzki, Claudia & Klier, U & Obst, W & Kreikemeyer, Bernd & Linnebacher, Michael. (2012). Reevaluating the Concept of Treating Experimental Tumors with a Mixed Bacterial Vaccine: Coley's Toxin. Clinical & developmental immunology. 2012. 230625. 10.1155/2012/230625.
(4) Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97. doi:10.1126/science.aan3706
(5) Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97-103. doi:10.1126/science.aan4236
(6) Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. 2020;368(6494):973-980. doi:10.1126/science.aay9189
