Designer bacteria have been genetically engineered to bolster the body’s immune response against tumours, Cancer Research UK scientists reveal in a report published this month1.
Researchers in Leeds added a gene to a strain of bacteria that is harmless despite being related to the bugs that cause tuberculosis. The extra gene makes the bacteria produce a molecule that boosts the immune system’s ability to identify and kill cancer cells.
In mice, the modified bacteria worked much better against tumours in the bladder than existing treatment. Although the research is still at an early stage, this enhanced bacterial strain could become a safer and more effective therapy for bladder cancer.
Current treatments for bladder cancer include BCG, the bacteria best known as a vaccine against tuberculosis. BCG is a neutralized strain of bacteria that has been used to treat bladder cancer since 1976. The bacteria are injected close to the tumours, and are thought to stimulate the local immune system, which then kills both cancer cells and bacteria.
This is a form of immunotherapy, a term which describes any therapy that recruits elements of the body’s own defence mechanisms to fight disease.
BCG does not work in about a third of patients with bladder cancer, despite being the most effective immunotherapy yet developed against any form of cancer. BCG can also cause significant unwanted side effects.
Researchers in the Cancer Research UK Clinical Centre at St James’s University Hospital, Leeds, aimed to improve both the safety and effectiveness of the treatment. They took harmless bacteria and added a gene to produce a protein called tumour necrosis factor alpha (TNFa).
TNFa is a part of the immune system, with a crucial role in killing unwanted cells, including cancer cells, and is produced in response to BCG.
In mice with bladder cancer, the new treatment led to a reduction in the size and number of tumours. Eighty per cent of the animals had no tumours by the end of the treatment.
Professor Peter Selby, Director of the Clinical Centre, says: “BCG works by enhancing the immune response. We’ve shown that by modifying a related bacterium, we can boost the immune system in such a way that it kills cancer cells even more effectively.
“Our report suggests important avenues for future clinical research. The safety of these bacteria would need to be formally verified before they could be tried in people, but the prospects are exciting.”
The strain of bacteria used in this research is called Mycobacterium smegmatis. Although related both to BCG and to the bugs that cause tuberculosis, infection with M. smegmatis is usually harmless.
This study is the first to show that live M. smegmatis has such an immunotherapeutic effect in bladder cancer. The results for unmodified M. smegmatis were comparable to BCG therapy; the genetically enhanced bacteria performed significantly better.
Professor John Toy, Cancer Research UK’s Medical Director, says: “Using the patient’s own immune system to fight cancer is becoming an increasingly promising approach. BCG has been in clinical use for bladder cancer for nearly 30 years but it doesn’t work in a third of patients and can have side effects, so it’s not ideal.
“This research combines genetics with immunotherapy to offer the hope of a new way to treat bladder cancer more safely and effectively.”
- International Journal of Cancer (2004) 112 (4) pp.653-660
Each year bladder cancer affects more than 12,500 people in the UK and accounts for nearly 5,000 deaths. It affects about two and a half times as many men as women, most cases developing after the age of 50.
BCG stands for ‘bacillus Calmette-Guerin’. This is an attenuated form of Mycobacterium bovis. Attenuated means the bacteria are still alive, but their toxicity has been reduced.
Mycobacterium is a genus of related bacteria. One species in this group is Mycobacterium tuberculosis, the cause of tuberculosis (TB).
M. bovis is closely related to M. tuberculosis, which is why its attenuated form is a good vaccine against TB. M. smegmatis is not as closely related, and is not as harmful.