We all dread these six letters.  C  A  N  C E  R.  The second largest killer of humans in advanced societies.

It conjures up images of pain and suffering- and that’s separate from the disease itself.  The irradiation treatments and  the chemotherapy create all kinds of pain and maladies within the patient- and that’s true even if the patient garners no benefit from the treatments.

And, we are always seeking out new methods to treat cancer.  Because our current modalities are only slightly better than hit or miss concepts.  Sure, we have some drugs that work- but “working” means that the cancer population is attenuated.  It is not usually eradicated- which is why those who’ve undergone these deadly treatments and survive are said to be in remission.  Not cured.

The problem with cancer is that the cancer cells are not really foreign invaders. So our immune system just passes these treacherous cells by.   So, we need to figure out how to “smarten up” our immune system.

One idea- clearly out of the box thinking- has been undertaken by a slew of very smart Korean scientists and by doctors in Germany and the US.  The Korean group is headed by Drs. JH Rhee and JJ Min of Chonnam National University (Jeonnam).   Along with Drs.  JH Zheng, VH Nguyen, SN Jiang, W Tan, SH Hong, MG Shin, IJ Chung, Y Hong, HS Bom, HE Choy, SE Lee (all from various Chonnam departments) and Dr SH Park (Korean Institute of Bioscience and Biotechnology), they’ve  published their creative concept in Science Translational Medicine.

Their article, Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin, provides the basic idea.  (You do recall that Salmonella are associated with food poisoning in humans, right?) The researchers have modified the Salmonella bacteria to trigger an immune response in other cells.  Now, we must recognize that this concept has only been tested in mice (and the researchers used human cancer cells in the mice, to boot).

It is the lipopolysaccharide deletion mutants that were chosen, because they possess the best tumor specificity- and the least pathogenicity. But, the microbes still needed to be modified to amplify their antitumor effects; this was done by adding an inducible arabinose promoter.

Way back in 2006, the Korean group began their search for a new cancer treatment.  Coincidentally, they were also hoping to find a way to protect (local) shellfish against Vibrio vulnifucus   That latter research provided them the serendipitous link they needed for the former.  They observed that the flagellum of the Vibrio microbe, used to let the microbe swim (via the whiplike motion of the flagellum) effected a strong response from immune cells  The researchers decided to “morph” the tail onto the (relatively) harmless  Salmonella typhimurium  and then they also  weaponized that tail so it would secrete a protein,  FlaB (to induce immune response).

The Salmonella microbe was chosen because, as a facultative anaerobe [it grows with or without oxygen], it is able to colonize solid tumors (these tumors leave necrotic, oxygen depleted tissue nearby to the tumors) AND to effect an intrinsic antitumor effect.  When the microbe is injected and colonizes the tumors, local macrophages (part of the immune response system) convert from an immunosuppressive (reduce the immune response) to a pro-inflammatory (active foreign body attacker) phenotype.

Injecting the microbe into 20 mice infected with human colon cancer cells, the researchers found that the mice no longer retained the microbes in the lungs, livers, and spleen after 3 days.  But, within their cancerous colon tissue, the microbes were flourishing.  117 days later (day 120), more than half (11) of the mice had no detectable cancer cells.  (The mice were also healthy.)  Mice injected with the Salmonella  that did not secrete FlaB died of their cancers.

The next set of experiments employed metastasizing human colon cancer cells.  Of the 21 mice, 8 were infected with FlaB secreting Salmonella; six were treated with non-FlaB secreters; the remaining seven were controls.  27 days later the controls and mice infected with the non-secreter strain had significant numbers of metastasized cells.  The 8 mice treated with FlaB Salmonella had four secondary tumors (in total)- and most had no metastasized cells.

The German/American group includes Drs. M Frahm, S Felgner, D. Kocijancic, M Rohde, M Erhardt, S Weiss (Hemholtz Center for Infection Research), M. Hensel,  (University of Onsabruk)  and Dr. Roy Curtis III (Biodesign Institute, Tempe AZ).  They published their findings in the journal mbio.  They used the same cells (but more carefully identified them as Salmonella enterica serovar Typhimurium). This group reports similar results as the Korean group.

Now, we should note that a long time ago (almost 126 years ago), Dr. William Coley (a bone surgeon) considered a similar approach to cancer treatment.  Considered to be the father of immunotherapy, this Memorial Sloan Kettering Cancer Center physician (ok, the hospital has morphed into this entity) had noted that one patient who had a virulent bacterial infection survived sarcoma for 7 years.  So, he tried the concept on others- initially with live Streptococcus (eventually switching to killed microbes), injecting the concoction into patients.  The inoculations spiked fevers, but a good number of the patients’ tumors shrank.

He perfected a vaccine (Coley’s toxin), which was sold by a variety of drug manufacturers.  But, two problems removed Coley’s toxin from routine practice.  First of all, the concoction was not manufactured in optimum conditions- nor was it routinely administered to patients properly- so the results became spotty.  Secondly, new inventions were coming to the fore.  And, Cooley’s toxin became forgotten.

Only to be reconsidered now…