Infections are a double-edged sword when it comes to cancer. On the one hand, infections are our foes. Several viruses, such as the human papillomavirus, are well known to produce pre-malignant lesions that may lead to the development of tumours. Chronic inflammation, which is sometimes caused by pathogens such as viruses and bacteria, has also been linked to cancer formation.
But there is another side to the relationship between cancer and infections, in which the latter can mediate tumour regression. This potential for pathogens to be our friends in the fight against cancer was again confirmed recently, when the results of a phase III clinical trial showed encouraging results in melanoma patients. In this study, the patients’ response to treatment was significantly improved when their tumours were injected with a genetically modified virus. But although it has not been well publicised, the idea of using pathogens as an anti-cancer weapon is not new and actually started more than a century ago.
Getting sicker before healing
In 1891 surgeon William B Coley started looking for alternative anti-cancer treatments. Devastated after a young patient he was treating succumbed to her cancer, a sarcoma in the right arm, Coley was determined to find a better way. He went back to old medical records and found observations describing cancer regression in patients who had experienced erysipelas, a skin infection induced by the streptococcus bacteria. Excited by this novel perspective, Coley treated his first patient in 1891 by injecting streptococcal cultures directly into the tumour. The patient subsequently developed a strong fever and almost died. He survived, however, and his tumour had completely vanished at the end of the bacterial attack. He remained well for another eight years before dying of a recurrence.
Coley then attempted to cure several of his sarcoma patients using this method, despite the high risk of succumbing to the treatment. Later on, to increase the safety of the technique, he switched to a mix of streptococcus and serratia, another strain of bacteria, that were killed by heat. These bacteria were no longer able to replicate and induce the disease erysipelas, however they could still illicit a strong immune response and local inflammation. As we now understand, this local inflammation, and the subsequent recruitment of immune cells to the tumour site, were the key components of this successful therapy. The method gave rise to Coley’s toxins, often cited as an example today of the first success of immunotherapy.
Bacterial anti-cancer therapy
Bladder cancer is another example of the successful use of bacteria against cancer. Around 70% of patients diagnosed with bladder cancer bear a non-muscle invasive cancer, which means the tumour is largely accessible from the inside of the bladder. In this case, minor surgery can be performed to remove the tumour. Unfortunately, the recurrence rate is very high in this form of cancer, ranging from 30-75% depending on the risk category.
It was in 1976 that the first article was published suggesting a protective effect of the intra-bladder injection of Bacillus Calmette-Guerin (BCG). BCG is most well-known for its use in vaccination against tuberculosis. The BCG vaccine is made from a bovine strain of the bacteria that has been attenuated through in-vitro culture for an extended period of time. Although generally no longer able to induce tuberculosis in healthy animals and humans, the vaccine still contains live bacteria. They can be grown and injected into the bladder.
This has been shown to reduce the chances of cancer relapse three years after treatment by two-fold, compared to bladder instillation of chemotherapy drugs. However, once again using live pathogens has its drawbacks, and the chances of adverse events such as irritated bladder and flu-like symptoms are high.
Viruses to the rescue
But bacteria are not the only micro-organism we can use against cancer. Some viruses have oncolytic properties (where it specifically infects and kills cancer cells), and additionally they can be easily made from scratch in the laboratory, thus allowing for easy genetic modification.
Viruses are a highly evolved type of infectious agent. When they enter a cell, they inject their genetic information into it – or in the case of the herpes virus, blasting in its DNA. The cell then uses that genetic information like its own, and produces the viral proteins it encodes for. This leads to the cell unknowingly making more and more viral particles, until it bursts. The newly made viruses can then go and infect a neighbouring cell.
Fortunately, our cells have evolved to “sense” viral entry into their cytoplasm and to react by either blocking their production of proteins, or committing suicide. This is a tightly regulated function called “programmed cell death”, which prevents the further spread of the virus.
The interesting thing when it comes to cancer is that the malignant cells have lost, through many genetic mutations, the ability to protect themselves against viruses, as well as to undergo programmed cell death. Their inability to die when they should is actually at the core of their malignancy. So using viruses can be a way to specifically target tumour cells, while healthy cells remain unharmed.
In the recent phase III clinical trial, talimogene laherparepvec (T-VEC) was used, which is a genetically modified herpes simplex virus (HSV). Normal HSV is highly evolved and has learned to hide from our cells’ viral sensors. But this therapeutic HSV has been genetically dulled to be efficiently controlled by healthy cells, but still able to infect tumour cells. Its ability to replicate, however, is not compromised – which means that a small dose of virus can keep infecting new targets until all tumours cells are gone. Moreover, it induces the expression of GM-CSF in the tumour cells, which is a factor that recruits immune cells to the tumour site. The effect of T-VEC is hence double: directly destroying the tumour cells, as well as attracting immune cells on site to finish up the job.
In comparison to the previous examples, this treatment was generally safer, with no treatment-related death, and few patients discontinuing therapy because of discomfort (4%). Moreover, the efficacy was unprecedented for this kind of therapy, as 16.3% of patients achieved remission for at least six months, compared to 2.1% receiving the control treatment. Interestingly, the benefits were even increased in the patients who had a milder severity of melanoma, as well as in the patients for whom it was the first line of treatment.
These data demonstrate the potential of microbial infection to enhance the immunotherapy of cancer, and pave the way for the development of new therapies in the field of oncology.
Gwennaëlle Monnot receives funding from the Swiss National Science Foundation.