Bacteria and viruses generally bring unpleasant thoughts to mind: having the flu, maybe, or food poisoning. However, these little guys have a positive place in our lives, like the microbes in our gut that keep us healthy. Amazingly, they may also hold the key to the future of cancer therapy. While scientists generally study human diseases in mice, rats, or even monkeys, nature’s tiniest beings have special properties we can learn from and harness for cancer treatment. Let’s go on a journey through three such examples – showing that when it comes to biological capability, size doesn’t matter.
1) Let’s delve into the kingdom of bacteria.
The concept, actually, is not new. There is a long history of attempts to use bacteria in cancer therapy. Over a century ago, medical scientists noticed that some of their patients’ tumors shrank after catching a Streptococcus infection. A surgeon named William Coley thought that perhaps the immune response to the infection helped attack the tumor as well. He took this theory a step further by injecting dead bacteria into his cancer patients, in the hope of getting the patient’s immune system to activate and start turning against the tumor. While there was some anecdotal evidence of success, there were also risks, including high fevers and other illness-like symptoms triggered by an active immune system.
Coley was on the right track, but with the wrong bacterium. While he and his colleagues used Streptococcus pyogenes and Serratia marcescens, a different bacterial strain could be safer and more effective. Recent studies used a bacterium called Clostridium novyi. Previous research had shown that C. novyi can destroy cancer cells by secreting digestive enzymes that chew up the tumor. But how do we protect normal cells in the body from the same fate? The answer: oxygen. C. novyi has the special property of being super sensitive to oxygen – these bacteria survive in conditions of low oxygen, but die in the higher oxygen levels that exist normally in our body. This is perfect for cancer treatment, because the cores of tumors are usually hypoxic – they are oxygen deprived. We therefore have an elegant system in which the bacteria can live in the core of a tumor, but will die elsewhere in the body, protecting the person from an actual bacterial infection. Just to be on the safe side, the bacteria were also genetically engineered to prevent production of particularly nasty toxins.
The authors of this study found that if you directly inject C. novyi spores into tumors, the tumor will stop growing, shrink, or disappear altogether (in 11 of the 14 cases studied in dogs). This success led them to a clinical trial: A woman was treated with an injection of C.novyi spores in one of her tumors, and within a few days the tumor began shrinking and dying! Although many more trials will have to be performed to assess safety and efficacy, this looks like a great start. The hypoxic core of a tumor will be eaten up by bacteria, and the remaining outer ring of the tumor exposed to oxygen can get destroyed by the immune system[AJ1] .
One caveat to this treatment method is that it works best when injected directly into a tumor; if metastases have spread too much throughout the body, it would be difficult to reach every tumor. On the other hand, a common problem with regular chemotherapy is delivery of a drug into the core of a tumor, since there isn’t an adequate blood supply to get it there – direct injection of bacteria would bypass this difficulty.
“Bacteriolytic therapy can generate a potent immune response against experimental tumors” http://www.pnas.org/content/101/42/15172.full
“Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses” http://stm.sciencemag.org/content/6/249/249ra111.full
2) Let’s take a look at viruses.
As with bacteria, several medical cases were observed in which cancer patients who contracted a viral infection exhibited tumor regression. Normal cells in our body tend to fight off viral invasion, but tumor cells often are unable to do so and get taken over and eventually killed by certain viruses. Additionally, scientists are now able to mutate a virus’s genome to make it even more specific to cancer cells – such that the virus would be unable to replicate in normal cells, but would attack tumor cells only. These are called “oncolytic viruses.”
The most recent success has been with an attenuated measles virus. A specific strain was developed that effectively causes tumor cells to stop growing and die, and it was engineered to contain an inert gene “tracker” to follow where the virus is going. The virus selectively targeted tumor cells and caused tumor regression while leaving normal cells intact. A clinical trial at the Mayo Clinic has treated a myeloma patient with this measles strain – and she has been cancer-free for a year.
“Intraperitoneal Therapy of Ovarian Cancer Using an Engineered Measles Virus 1” http://cancerres.aacrjournals.org/content/62/16/4656.full
3) Our final story returns to bacteria.
The concept is called “magnetic hyperthermia,” and here’s how it works: Iron particles are injected into a patient’s bloodstream, and they enter a tumor through leaky blood vessels typically associated with malignant tissue. The patient then goes into an MRI machine, and the magnetic field inside the machine is rapidly alternated, causing the poles of the iron particles to flip over and over. This process generates heat, and the tumor is essentially fried from the inside out.
Unfortunately, there are some technical difficulties: iron nanoparticles get too diluted in the bloodstream, so there needs to be a way to target them to the tumor. Direct injection into a tumor is a possibility, but limited – hard-to-reach tumors or small metastases would be missed. Even more problematic, it was shown that iron nanoparticles’ ability to heat up dropped dramatically once it actually got inside a cell. Direct iron injection would only be efficient in the extracellular environment.
Amazingly, the solution may be found by studying certain species of bacteria – which are naturally magnetic! Evolution has equipped these organisms to use the earth’s magnetic field for navigation, and they do so by encoding genes responsible for accumulating magnetic iron particles inside the bacteria themselves. Scientists have now found a way to mimic this bacterial property in bacterial strains safe for humans. The strain chosen, Lactobacillus fermentum, is a probiotic strain naturally living in our microbiome. By assembling magnetic clusters on Lactobacillus cell surfaces, they achieved an artificially magnetic bacterial strain. Iron particles loaded onto bacteria are much more efficient at generating heat than are free iron clusters. Lactobacillus’s probiotic property makes them able to be ingested, digested, and to easily reach any tumors in the GI tract. Since these bacteria prefer hypoxic areas, the hope is that they will be able to travel through the body and localize in the core of non-GI tumors as well. Using magnetic bacteria is also much safer than injecting free iron, which can be toxic to organs if accumulated at unsafely high concentrations.
“Magnetic hyperthermia efficiency in the cellular environment for different nanoparticle designs” http://www.sciencedirect.com/science/article/pii/S0142961214004232
“An Iron-regulated Gene, magA, Encoding an Iron Transport Protein of Magnetospirillum sp. Strain AMB-1” http://www.jbc.org/content/270/47/28392.full
“Artificial Magnetic Bacteria: Living Magnets at Room Temperature” http://onlinelibrary.wiley.com/doi/10.1002/adfm.201303754/abstract
The amazing thing about these methods of treatment is that they are theoretically effective against all cancers. A lot of attention these days is focused toward tailoring a different treatment regimen to each of the myriad types of cancers – and distinguishing treatments even further depending on the mutational background of a cancer subtype. While specificity could no doubt be effective, it requires mutational profiling of every patient’s tumors and is a messier approach. Bacteria and viruses are certainly not “silver bullets” for cancer therapy yet, but this looks like a good start.