Health

Cancer researchers have turned to a largely forgotten treatment developed in the 1890s, injecting bacteria into tumours. By Wendy Zukerman.

Cancer-eating bacteria a throwback to old-time medicine

Bert Vogelstein, of Johns Hopkins University, Baltimore.
Credit: Graham MacIndoe

The surgeon sucked bacteria into the syringe and plunged it deep into his patient. It was the 1890s, almost 30 years before antibiotics would be discovered. Colleagues observed with “chilling scepticism” and “natural distrust”. But the doctor, William Coley, persisted – infecting more than 100 patients in the next four decades with bacteria. As onlookers scoffed, Coley kept his eyes on the prize – describing his own work as “nothing short of marvellous”.

Coley was pioneering a new treatment for cancer, stabbing bacteria into tumours in the hope that the infection, and ensuing fever, would kill the scourge. In a presentation given to the fellows of the Royal Society of Medicine in London in 1909, he described “absolutely hopeless” cases of “inoperable” cancers that “entirely disappeared” following his treatment. Marvellous indeed. His audience, however, was unconvinced, alluding to the treatment as “quack medicine”.

By the turn of the century, radiation, and later chemotherapy, came into vogue. “Bacteria-based therapy fell completely by the wayside,” says Saurabh Saha of BioMed Valley Discoveries in Kansas City.

But today, scientists such as Saha are renewing Coley’s work. Earlier this year Saha, and colleagues at Johns Hopkins University in Baltimore, announced that one woman’s tumour had shrunk significantly after being injected with bacteria. Trials with more patients are now under way.

The move is sparking calls to look further into medical annals for more quackery. “Our attention span is always on the next greatest thing, and we don’t look back,” says Saha.”If we were better historians we would probably have more effective treatments for cancers.”

While modern cancer treatments extend lives and reduce side effects, there are many pitfalls. Chemotherapy and radiation, for example, often can’t get inside the centre of solid tumours to eradicate the cancer, which means it is able to regrow. This is because few blood vessels venture into the heart of tumours, leaving their centre with little oxygen. Chemotherapy agents need blood vessels to infiltrate tumours, while radiation therapy requires oxygen to create free radicals that will kill tumours.

With frustrations at conventional approaches mounting, Bert Vogelstein at Johns Hopkins University went to the history books. He pored over the literature, searching for radical methods that could destroy cancer. Coley’s work looked promising.

It was difficult to know how promising, however. While some now describe Coley’s treatment as remarkable, his publications are not written to today’s standards and it’s unclear how many patients died after submitting to the radical procedure. In his 1909 speech Coley acknowledges failures, noting “that only a few, instead of the majority, showed such brilliant results”. Still, he was clearly onto something. In a recent review of the topic in Nature, the University of Milan’s Alberto Mantovani and his colleagues wrote that Coley “documented cases of the long-term survival of individuals with malignancies that remain a major challenge to treat now”.

Over time, Coley experimented with various types of bacteria, but Vogelstein figured he might improve the surgeon’s mixed results using modern techniques to find the best cancer-killing bacteria. He screened scores of bugs and one came out the winner: Clostridium novyi, a potentially lethal bacteria found in soil.

Vogelstein set to work, heating the bacteria to remove a particularly nasty toxin. Next, his team injected it into cancers of rodents and rabbits. They found the Clostridium bug was adept at killing tumours. It secreted enzymes that fed on, and destroyed, the cancer cells.

A major advantage of Clostridium novyi came from its origins. Naturally living deep in the soil meant the bug thrived in environments of extremely low oxygen. Hence the bacteria could penetrate the hitherto impermeable heartland of the tumour, and was less likely to escape and infect healthy and oxygen-rich areas of the body. When the team injected it into animals they reported it would “germinate exclusively” within the sought-after low-oxygen regions.

There was another advantage to injecting the foreign bacteria: it encouraged an onslaught of immune cells to the tumour site, which attacked the cancer as they would a bacteria or virus. This, in itself, is noteworthy. Traditionally, cancer cells were thought to be invisible to the immune system because they aren’t alien. But over the past few decades scientists realised that immune cells do get attracted to cancers, although the response isn’t large enough to destroy them. Injecting bacteria into the belly of the tumour, however, rouses an efficient immune offensive.

After success in Petri dishes, rodents and rabbits it was still uncertain whether Clostridium novyi would destroy human tumours. Cancer cells in people have different genetic mutations to those of other animals, in some cases even evolving methods to protect themselves against immune responses. It was time to repeat the quackery conducted over a century ago. Scientists at BioMed Valley Discoveries, now collaborating with Vogelstein, filled a syringe with bacteria and injected it into a patient.

Their test case was a 53-year-old woman with tumours in her liver, lungs and right shoulder, who hadn’t responded to conventional cancer treatments. Within days of the injection, scans and biopsies showed the bacteria entered the tumour and was destroying cancer cells. One month later, her cancer had shrunk so significantly that she regained movement in her shoulder. In August, the results were reported in Science Translational Medicine. Buoyed by the success, the team are now injecting bacteria into more patients.

“I was amazed,” says Michael Parker at the University of Melbourne, who was not involved in the study. He says these tumours are “very difficult to treat” and the results are promising.

But with cancer, it seems, there is no silver bullet. Cancers can spread to other parts of the body in a process called metastasis. Since the bacteria do not travel easily outside the low-oxygen belly of the tumour, it will not attack these distant tumours. Indeed, the woman in this study ultimately died from remaining uninjected tumours.

Even after treatment, chemotherapy would be required. Animal studies by Vogelstein’s group found that the bacteria only wipe out cancers in about 30 per cent of cases. This is likely to be because of the way the bacteria attack the very centre of the tumour, but not the edges where oxygen levels are higher, says Parker.

There are also concerns about the safety of injecting Clostridium novyi. The woman in the trial experienced pain in her shoulder and so much inflammation in her arm that the fluids needed to be drained. Of course, if there is no alternative, such side effects are likely to be acceptable.

Uwe Hobohm, a cell biologist at the University of Applied Sciences in Giessen, Germany, says it is difficult to get regulatory approval for the use of live, potentially dangerous, bacteria. According to Hobohm, regulatory bodies usually demand treatments with pure chemicals and clearly defined modes of action. This is why he and others are working on unravelling precisely how the bacteria destroy tumours in a bid to mimic their actions in targeted products. For example, Hobohm is using specific substances found on bacteria and viruses called pattern recognition receptor ligands to stimulate the immune system. He’s had success with mice.

Another approach, adopted by Canadian pharmaceutical company MBVax Bioscience, is to use dead strains of bacteria to target cancers. The team inject dead Streptococcus and Serratia marcescens, a recipe Coley himself used. According to their own figures, MBVax has seen improvement in about 70 per cent of its patients. Since the bacteria are dead, they don’t chew up the cancer, like Clostridium novyi, but act ”solely by sparking the immune system”, says Stephen Caan, the chief medical officer of MBVax. He acknowledges this is sometimes not enough to control the cancers.

Elsewhere Big Pharma are forgoing bacteria and focusing on drugs that encourage the immune system to kill tumours. In September, Merck’s drug pembrolizumab was approved by the US Food and Drug Administration for use in melanoma. The drug tinkers with the immune’s regulatory system, inciting cells to attack tumours. While the approach is promising, only 24 per cent of patients initially responded to the treatment, and its long-term effectiveness remains unclear.

“We’ve been trying to fight cancer for over a century, but there is so much left to do,” says Saha. But, with optimism, he says there are likely to be other promising treatments hidden in dusty pages of medical history. “I’m sure there are more of these ideas buried away, undiscovered.”

This article was first published in the print edition of The Saturday Paper on Oct 25, 2014 as "Old-time medicine". Subscribe here.

Wendy Zukerman
is a science journalist and host of the Science Vs. podcast.

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