"Remote-controlled" Salmonella as anti-cancer agent
HZI scientists developed an alternative approach for tumor therapy
Cancer therapy involving bacterial infections? This sounds risky when you first think about it and many dangerous pathogens are indeed not the agent of choice in the fight against cancer. Though they may cause solid tumours to go into remission, they are harmful to the patient as well. Other bacteria might be harmless for the patient, but are also ineffective against cancer. Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig recently modified Salmonella such that they possess an aggressive anti-tumour effect - initially. They later turn this activity off and can then be eliminated by the immune system: The perfect balance for a new form of therapy.
Cancer is the second-most common cause of death in the Western world. Despite the progress that has been made in established treatments, such as irradiation or chemotherapy, the incidence of disease is on the rise. Therefore, there is an urgent need for new ideas for new forms of therapy. These might require new approaches which, at first glance, might be expected to worsen the condition of the patient. This certainly applies to the bacteria-mediated tumour therapy developed at the HZI. Indeed, this method is a balancing act. "In this treatment, we cannot work with bacteria that are absolutely harmless. But hazardous pathogens are too risky," says Dr Siegfried Weiß, who is head of the Molecular Immunology research group at the HZI. "We just had to find the right balance."
Injected into a vein, Salmonella elicits a spontaneous immune reaction in the body. Many cells of the immune system recognise the intruders immediately and alert the body through the release of messenger substances. "This leads to an interruption of the oxygen supply in the tumour. In addition, the tumour is colonised by the bacteria," says Weiß. This treatment often leads to complete remission of tumours in mice. However, the aggressive nature of Salmonella is often a more substantial problem for the animals than the cancer itself.
The scientists discovered that the response of the immune system depends on a surface molecule of the Salmonellae called lipopolysaccharide (LPS). This long-chain molecule is responsible both for the hazard posed by a pathogen and for its ability to resist the immune system. "Even if the bacteria are taken up by immune cells, they managed not to be eliminated, which usually happens in this location. They can even proliferate in the cells. This allows the infection to spread," says Dr Michael Frahm, who is the first author of the study published in the professional journal, mBio.
For this reason, the scientists tested less harmful variants for their effectiveness against tumours. "Initially, we repeated the therapy with genetically-modified Salmonella, whose LPS chains had been artificially shortened," says Weiß. "But we observed that the attenuated bacteria also lost their anti-tumour effect. This made us think of remote-controlling the aggressiveness of the bacteria."
Frahm and his colleague Sebastian Felgner then modified the Salmonella strain appropriately such that they grow like the original Salmonella in a nutrient medium only in the presence of a certain sugar. But as soon as they are injected and the sugar is absent, they convert into the more harmless variant within a few hours. "What is special about this is that the immune system initially response very strongly, but is later able to eliminate the bacteria which are harmless by this time. But the bacteria still infiltrate the tumour," says Frahm. Since the Salmonella lose their aggressiveness, this is associated with only minor complications. While the anti-tumour effect persists.
The next aim is to further investigate and optimise this approach. "The path to clinical application is still very long, but it is very promising as well," says Weiß.
Michael Frahm, Sebastian Felgner, Dino Kocijancic, Manfred Rohde, Michael Hensel, Roy Curtiss III, Marc Erhardt, Siegfried Weiss.Efficiency of Conditionally Attenuated Salmonella enterica Serovar Typhimurium in Bacterium-Mediated Tumor Therapy. mBio, 2015, DOI: 10.1128/mBio.00254-15.