Using TB to Fight Cancer: Using One Formerly-Deadly Disease to Fight Another

A friend of mine mentioned to me at dinner a few weeks ago that one of her relatives was undergoing cancer treatment, which involved him being infected with tuberculosis. This immediately peaked my interest, because as a former cancer researcher, I was super curious about how a bacterial infection could help defeat cancer cells. Several hours of research later, this is what I found out:

Cancer is a disease in which normal cells are mutated (their genes are changed), with the result that they now grow out of control. Because they are reproducing quickly, they also take up a lot of the body's resources (oxygen, food, etc.), not to mention space. (To the Star Trek geeks out there, cancer cells are basically Tribbles.) These cells have also lost the ability to do whatever specific job the cell originally had. The body usually operates with the motto "a place for everything and everything in its place"; cancer cells are the ever-multiplying clutter that are destroying the orderly filing system.

Tuberculosis is primarily a lung infection, caused by Mycobacterium tuberculosis, a type of bacteria. What makes TB special is that it is a rare bacteria that infects inside human cells; the bacteria enter certain cell types in the lungs, and use the cell machinery to help them divide. This is the mechanism used by viruses, but most bacteria cause their damage without having to enter cells. (For instance, pertussis, i.e. whooping cough, causes its damage by releasing a toxin into the upper airway; many types of food poisoning do the same in the intestine). Because the bacteria infect inside the cells, the body has to use a different immune response than it would use to fight off most kinds of bacteria. [For anyone who has had a TB skin test, this is why the test (which involves injecting an ineffective type of TB under the skin, and waiting three days to see if a bump appears) takes so long to read; the immune reaction against intracellular infections takes longer for the body to activate, but then results in a lot of multiplication of immune cells (which is what causes the bump).]

Because TB was such a deadly disease, doctors tried to develop an effective vaccine. The best vaccine currently available uses BCG, a modified form of a tuberculosis bacterium (or, rather, a modified form of the bacteria that causes TB in cows). BCG is an "attenuated" bacteria, meaning that it is still alive, but is very weak and not very good at infecting people. This means it should activate the immune system without actually hurting the person. This vaccine offers variable levels of protection against the disease. It is no longer used in North America, because incidence of the disease is low already, the effectiveness of the vaccine is in question, infections can be treated with antibiotics, and people who have received the vaccine can no longer be tested using the TB skin test. (The reason is that the skin test tests immunity to the bacteria. In patients who have never been vaccinated, any immunity to the bacteria suggests that they are, or have been, infected with the bacteria. In patients who have been vaccinated, the immunity may be due to the vaccine, which makes it unhelpful for testing whether there is also a current infection.)

Back in the early 1900s, doctors started to notice that tuberculosis patients seemed to have lower incidents of cancer, and that, compared to the population at large, the minority of TB patients who did develop cancer showed a higher rate of remission (i.e. they were more likely to have their cancer recede to undetectable levels). This correlation actually got turned into treatment; and, in fact, the leading treatment for early-stage bladder cancer, following surgical removal of the tumour, is to fill the bladder with BCG, the same bacteria used in the vaccine. The medical field still isn't 100% sure why this treatment works, but their best guess is that the bacteria is stimulating the immune system and making the immune system better at fighting off the cancer. Our immune system can detect two different kinds of dangers. One is intracellular dangers - infections that get inside our own body's cells, such as viruses, and some bacteria like TB. The other is extracellular dangers, like most bacteria and toxins (and allergens), that don't get into cells but need to be fought off in the blood/intestines/airways. Cancer cells can be detected and killed by the intracellular danger pathway, because the mutations which have caused the cells to turn to cancer are viewed as a danger in the cell. However, tumours are also really good at tricking the immune system into thinking there's actually an extracellular instead, so that the tumour cells get ignored.

Because TB is an intracellular danger, adding tuberculosis bacteria to the cancer site forces the immune system back into the intracellular danger pathway, which makes it easier for the immune system to notice, and thus fight off, the cancer. Pretty nifty stuff!

References

For those interested, I used the following articles as the basis for this description:

1. Herr HW & Morales A. History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story. J Urol 179: 53-56, 2008. This article is a history of BCG treatment of bladder cancer.
2. Liu WM, et al. Supernatants from lymphocytes stimulated with Bacillus Calmette-Guerin can modify the antigenicity of tumours and stimulate allogeneic T-cell responses. Br J Cancer 105: 687-693, 2011. This lab did studies on cancer cell lines (cells grown in the lab, originally derived from a patient culture but which has likely modified itself to survive growing in a dish) to try and figure out how/why BCG priming might help the immune system recognize cancers, and what cell signaling pathways are involved. I think they overstated their conclusions, but nonetheless there are pretty impressive data showing that the BCG treatment upregulates cell killing and increases the immune system's ability to detect the cancer cells.