The tumour’s roots are growing deeper. From beneath the tumescent, coral-like growth sprouting out of the bladder’s inner wall, they’ll soon reach the lamina propria – a type of connective tissue rich in fibroblasts and white blood cells – before penetrating into the layer of muscle that allows the patient to urinate. If the progress of the tumour has not been halted at this point, the cancer will spread into the peritoneal cavity and thereafter into the rest of the body.
Urothelial carcinoma, or bladder cancer as it is more commonly known, is the ninthmost diagnosed cancer in the world. The treatment of first resort is to have a surgeon perform a transurethral resection, involving the insertion through the urethra of a cystoscope into the bladder. Using a tiny camera mounted on the end of the instrument to pinpoint the location of any tumours, the surgeon passes a tool down the cytoscope to scrape the growths off the outer lining of the organ. Any open wounds are then cauterised with an electric current.
If this doesn’t work, then the organ is flushed with bacillus calmette-guerin (BCG), a drug derived from the bacterium that causes tuberculosis in cows. In human bladders, it is used to trigger an immunological response against any cancer cells present in the organ. If it fails to do this, however – the recurrence rate of bladder cancer is approximately 25% after a year and doubles after two years – and the disease does not respond to another round of BCG, then the organ is removed. “It’s a fairly tough procedure,” says Roger Dumoulin-White, the founder and CEO of biotech firm Theralase.
“They give the patient what’s called an ileal conduit, [where] they reform the urethra through the side of the tummy. You’d be urinating through a bag for the rest of our life, so the quality of life isn’t the best.”
Dumoulin-White, however, believes an alternative is in the offing. At its labs across the US, Theralase has been experimenting for just over a decade with photodynamic compounds that, when inserted into the interior of the bladder, home in on cancer cells. Once illuminated with green laser light, the compounds then set to work destroying the tumours, root and stem. The whole procedure lasts just under two hours and early data from clinical trials looks promising.
Light therapy
“I think the old adage is that it takes ten years of hard work to make an overnight success,” says Dumoulin-White. He’s only half joking. He first heard about the role lasers could play in healing tissue in the early 1990s, when he was a product team manager for a division of Ford. It was during a conversation with his father.
“He had called me up one day and said that he had found this new technology,” recalls Dumoulin-White. It was a laser that could supposedly heal tissue. His father set up a small demonstration at the family jewellery shop in downtown Toronto. “He produced this rudimentary product that he had obtained from Belgium, and proceeded to turn it on and put it on his arm. I snatched it out of his hand and said, ‘Dad, it’s a laser, it’ll burn you. What are you doing?’ He said, ‘No, no, no, it heals tissue.’”
The technology itself dated from the 1950s, the era of ‘going steady’, Buck Rogers, and ‘mutually assured destruction’. The recent invention of hot lasers had led scientists on both sides of the Iron Curtain to explore their potential as weapons of war. It was with this purpose in mind that Dr Endre Mester, a Hungarian physicist, began experimenting with a ruby laser to see if it caused cancer in animal specimens.
“He took a bunch of mice and shaved them, then he lasered them,” explains Dumoulin-White. “But what he discovered was that the hair on the animals that were lasered grew at a faster rate compared with the control animals.”
By the 1970s, research into the healing properties of lasers had spread to East Germany and the Soviet Union, before hopping over the Iron Curtain. “It was very low powered [and] it was not well understood,” says Dumoulin-White. “In the 90s, it started to expand more into Europe and made its first inroads into Canada, and that’s where I heard about the technology.”
Entranced by the possibilities of laserbased healthcare, Dumoulin-White promptly ditched his promising career at Ford and began Theralase from scratch. By the early 2000s, he was using it to commercialise cold laser therapy for muscle strain injuries, a business that has sustained the company well over the past decade. In that time, Dumoulin-White and his colleagues hit upon another way in which lasers could potentially revolutionise care: photodynamic therapy for cancer patients.
“I was reading an article in Laser Focus World,” he says. There were two lines “about a chemistry professor out of Virginia Tech [called Karen Brewer] who was just starting to develop compounds that were metal-based, had an affinity for cancer cells and could be light-activated.”
Photodynamic therapy works by inserting a special compound, known as a photosynthesiser, into the affected organ. This compound is absorbed by healthy and cancerous cells, but lingers for a lot longer in and around tumours. Once doctors are confident that the compound is only present in cancerous cells, the organ is illuminated using a laser or an internally delivered light source, ‘activating’ the photosynthesiser. Having latched onto the cancerous cell, the compound will react to the light by either producing an active form of oxygen that will destroy the cancer cell or triggering an immunological response against the tumours present in the affected organ.
Inhibitive cures
Dumoulin-White quickly snapped up the worldwide exclusive rights to Brewer’s research, while the chemist set about making the kinds of compounds that would turn her theories into reality. It was slow going. “I think Karen produced about one compound a year,” says Dumoulin-White, partly because of the exhaustive process of evaluating the characteristics of each photosynthesiser. “That was all fine and it was going well, but it was slow and it was expensive, and it was hard to fund because there was no revenue associated with it.”
After several years of work, however, the team at Theralase achieved a milestone, winning the 2010 Breakthrough Award from science journal Popular Mechanics. The resulting publicity saw another chemist, Dr Sherri MacFarland, offer up her research into rufinium and osmium-based photosynthesisers. “We set up a project where she started to manufacture some compounds and she could produce them much faster,” says Dumoulin- White. MacFarland was able to produce the compounds at the rate of three or four a year. The photosynthesiser that Theralase is currently testing in clinical trials, TLD-1433, is one of these rufiniumbased compounds. “We took it through a number of different models,” Dumoulin- White says. “We liked the results and so we entered it into clinical study.”
The procedure developed by Theralase is designed to treat non-muscle invasive bladder cancer through an intervascular installation of TLD-1433 into the bladder via a catheter. “That way, you’d get a distribution of the drug directly to the bladder cancer and not to the muscle wall, which surrounds the bladder,” explains Dumoulin-White. The firm has also customised the amount of the drug for each patient, to allow an even distribution throughout the inner lining of the organ. “We also use a voiding diary so we know how much urine, or how much liquid, the bladder can hold.”
After about an hour in which TLD-1433 is absorbed by the bladder cancer cells, an instrument Theralase calls the dosimetry fibre-optic cage is inserted into the organ via the urethra and unfurled like an umbrella. “We deploy our system, which is a fibre-optic assembly – so it looks like a whole bunch of monofilament fishing line – [and] then expand the cage inside the bladder,” explains Dumoulin-White. Optodes that detect the approximate light dose at 12 different locations in the bladder proceed to line up. “We then turn the laser on at a low setting and adjust the emitter, so it’s in the geometric centre.”
This can take a little time – bladders are the shape of pears, or hourglasses, rather than the footballs of popular imagination – but once the device is in position, the laser is switched on at full power and emits light in the range of 3W. “From there, we can look at the amount of cumulative light that’s being deposited or picked up by each of the detectors,” says Dumoulin- White. “By using even distribution of the light…you’re going to get a predictable activation of that drug.”
By using green light, the drug is only activated at a penetration depth of up to 0.75mm, avoiding the possibility of reaching into the bladder’s outer muscle layer. Once the light is switched on, TLD- 1433 goes to work by emitting a special type of oxygen that triggers natural cell death in the tumours. Dumoulin- White calls it “a different way of using” photodynamic compounds. “The drug we’ve used has a clear absorption in the bladder cancer lesions versus healthy urithelium,” he says.
Once this is complete, the bladder is voided and the cytoscope used to insert the fibre-optic cage removed. In total, the procedure can take up to two hours and, according to Dumoulin-White, preliminary results from phase 1B clinical trials appear promising. “The patients responded very well,” he says, bar the appearance of a mysterious red patch on one individual, the cause of which is still being investigated. Early toxicology analysis showed that the drug was completely removed from patients’ bodies within seven days.
Trial strength
Going forward, Dumoulin-White and his colleagues at Theralase only anticipate minor changes as they complete the first phase of trials in 2018. They’re already looking ahead to phase two trials across the US and Canada, as well as other applications for the drug. “At this stage, it’s [limited to] non-muscle invasive bladder, brain and lung cancers,” says Dumoulin- White. “But there may be other cancers that we can go forward with. We’ve had very strong pre-clinical data with numerous cancers, including breast, prostate, colo-rectal [and] pancreatic.”
For the moment, however, Theralase’s CEO is content with the current applications of the drug: talk is cheap, but funding aggressive expansion into new cancer treatments requires massive investment, something that will only come with the kind of proof of concept that TLD- 1433 is intended to provide. Dumoulin- White is firmly convinced that it will.
He harks back to that idea that it takes ten years of hard work to make an overnight success. And after 14 years of investment and research into this new procedure, the quality of life for thousands of patients diagnosed with bladder cancer depends on it.
