Episode 10

Less than two years after starting the transition from local research company into global enterprise, X-ZELL is about to celebrate our biggest milestone yet – the long-anticipated world premiere of the X-ZELL Cryoimmunostaining™ Suite, to be held at MEDLAB 2019 in Singapore from 26-28 March.

As the world’s first and only slide-based, 9-colour immunostaining system, Cryoimmunostaining™ has the potential to fundamentally disrupt the way the think about immunofluorescence cytology and could pave the way for exciting new research across a wide range of disciplines.

Amid the hype, however, we mustn’t lose focus of what has defined the X-ZELL brand from day one – a fierce commitment to questioning the status quo in pursuit of a world in which health is a reality for all, not a privilege for a select few.

With that in mind, the true reason why we do what we do is not to cause systemic disruption – even though it might be one consequence of our work – but to make health accessible for anyone, anywhere, regardless of income or social context.

It’s what helped us define our collective vision to create a world with zero deaths due to undetected cancer, and it will continue to guide us into the future. But, why cancer?

Statistics show that fighting cancer is key to championing health

The reason why our commitment to health as an elementary human right has led us toward fighting the world’s second-most dangerous disease (trailing only heart disease) is best explained by approaching the concept of healthcare from a macro perspective.

In taking on a bird’s eye view, it’s undeniable that the most fundamental milestones in the history of healthcare have occurred in recent history. They can largely be attributed to the invention of vaccinations in the 19th century, the discovery of penicillin in 1928 and the mass adoption of hygiene during the 20th century – three breakthrough discoveries that changed the very course of history and saved millions of lives.

At X-ZELL, we believe the next breakthrough to achieve comparable scale will be mastering cancer. According to the International Agency for Research on Cancer (IARC), a specialized research unit of the World Health Organization (WHO), it is now the most pressing health threat in the world, with one in five men and one in six women developing it during their lifetime.

Put differently, some 50 million people worldwide are battling some form of cancer as you read these words. Statistically, one in eight men and one in 11 women will die from it. That’s close to 10 million deaths in 2019 alone.

To us, these statistics read like a call to action – if we are serious about making health accessible at scale, controlling the global cancer epidemic must be our collective priority. The same view is shared by the European Parliament, which has recently re-established talks about population-based screening for some cancers.

Doing so, however, is a question that can only be answered at a micro level – literally.

Early detection is key to fighting cancer at scale

While most cancers can be cured if the respective tumours are removed before they metastasize (stages 1 and 2), intercepting them at the right time is a complex challenge that can be affected by dozens of variables.

Traditionally, cancer diagnoses are made by obtaining tissue samples from the suspected area and analysing them in a pathology lab.

While science is in agreement about the effectiveness of the process itself – despite significant downsides, the tissue biopsy is globally referred to as the gold standard – the question how and when to select patients for the procedure is still hotly debated.

Research has shown time and again that screening patients by analysing family history, age and potential symptoms may not be enough to warrant surgically removing tissue.

To reduce the risk of false alarms – and with it exposing the patient to unnecessary risk – researchers are searching feverishly for screening solutions that slot in between general anamnesis and laboratory testing without missing potentially harmful cases.

Many of them are specific to a certain type of cancer, but all of them share the same goal – intercepting clinically relevant disease when it’s still curable.

As a result, all of them will ultimately be compared to the gold standard. Only if they funnel the right cases through to the pathology lab will they gain widespread acceptance in the medical community.

Prostate cancer is the perfect case study

Prostate cancer is the perfect example to illustrate just how complex the issue truly is. Despite being the second most prevalent cancer in the world (age-standardized incidence, Globocan), physicians still don’t have a reliable way of testing men for the disease.

Since the early 1990s, selecting patients for biopsy has relied heavily on Prostate-Specific Antigen (PSA) testing, an affordable and widely accessible solution that continues to divide the urology community due to its low diagnostic accuracy in the so-called PSA grey zone.

Often described as ranging from 4-10ng/mL, with some studies expanding it to 4-20ng/mL, it leads to at least half of all prostate biopsies to be performed on healthy men. 

A second much-debated shortcoming of PSA-driven diagnostics is the risk of exposing clinically insignificant cancers that remain asymptomatic during thepatient’s lifetime, also known as “over-diagnosis”. A significant portion of patients still undergo biopsy without clinical benefit, yet suffer from complications such as bleeding, infection and sepsis.

In a move to overcome these limitations, research has recently focused on finding adjunct tests to slot in between PSA and tissue biopsy. Ideally, such a tool would improve PSA’s low positive predictive value (PPV, the probability that aggressive prostate cancer is present) while offering a high negative predictive value (NPV, the probability that aggressive cancer is absent) to confidently rule out unnecessary tissue biopsies.

Well-published attempts to create such a tool include the PHI assay and the 4Kscore Test, both relying on combinations of PSA and PSA precursors as well as clinical information. Circulating DNA, miRNA as well as urine tests for various analytes are reportedly also under development. To date, however, none of these alternatives has gained notable traction in clinical routine.

On the more costly end of the scale, Magnetic Resonance Imaging (MRI) has also been discussed as a potential PSA add-on. But there are downsides too. The recent PROMIS trial, for example, reported a relatively low NPV of 76 per cent for clinically disease, meaning it can’t confidently rule it out.

In addition, MRI is also restricted by high cost, limited accessibility and reliance on the PI-RADS reporting system, which suffers from significant inter-observer variability – meaning different operators interpret the same image differently.

With all that in mind, prostate cancer is a prime example to illustrate just how complex it is to find an early detection solution that is sufficiently accurate to avoid putting patient health at risk, but also economically viable and scalable around the world.

At X-ZELL, we believe the key to triaging the right patients to biopsy lies hidden within our very own blood stream – specifically in a new class of circulating biomarkers that have long been considered impossible to detect in clinical routine.

Our research on prostate cancer patients has shown that by scanning small blood samples fortumour-derived Circulating Endothelial Cells (tCEC), we can not only detect cancer early, but also to differentiate between aggressive and dormant disease. After all, 30 years of PSA testing have demonstrated impressively how taking premature action on benign disease can be just as dangerous as taking no action at all.

Importantly, we believe tCEC testing will not only benefit prostate cancer patients, but also solve comparable issues in other cancers.

Why tCEC hold the key to cancer screening

The reason why we pursue a tCEC-based approach over alternatives such as DNA sequencing to make safe and reliable cancer screening accessible to everyone is two-fold.

For one, we believe that holding on to the millennia-old tradition of pathology will fast-track global adoption because we can build on an existing, well researched knowledge base and slot neatly into existing workflows. Same staff, same principles, different application.

Put differently, if pathology is the current gold standard to confirm a cancer diagnosis via tissue analysis, why not apply he same knowledge to pre-selecting patients – especially given there is no indication that any of the long-standing gold standards will be challenged any time soon?

Key to scaling processes quickly – read: to help as many people as quickly as possible – are consistency in training, access to experienced staff and full trustworthiness among the medical community. Right now, only pathology-based processes can tick all of these boxes.

Secondly, it cannot be overstated that tCEC might hold the key to distinguishing clinically significant from insignificant disease, and with it to safeguarding patients’ mental health.

The reasoning behind it is simple – if cancers are detected before the respective diagnostic gold standard is able to confirm a diagnosis, both patients and health professionals can be caught in a dangerous limbo as most existing early detection technologies are too inaccurate to truly confirm or rule out the presence of clinically significant disease.

The result is that in most cases, pathology will have to step in anyway. Most often, that would involve highly invasive procedures to obtain tissue samples for laboratory review – all based on what could be false alarms.

The unique characteristics of tCEC (more on that here) not only overcome that problem, but do so by providing real-life visuals of cell architecture and morphology – allowing a cell sample to be identified efficiently as malignant or benign according to stringent cytological criteria.

Why alternatives don’t work

The most commonly used biomarker in the early detection space is circulating tumour DNA (ctDNA) – tumour-derived, fragmented DNA that is traveling freely in the bloodstream.

Albeit promising, research has shown that robust ctDNA samples are hard to obtain in clinical routine – both quantitatively and qualitatively – and that there is still a significant risk of false-negative and false-positive results associated with them.

According to Eleftherios Diamandis, a professor of clinical biochemistry at the University of Toronto, one reason DNA is underperforming in early detection is that there is simply not much ctDNA to detect when the tumour is small.

“Last year, [Diamandis] and his associate Clare Fiala published a series of journal pieces questioning how useful ctDNA could really be in early cancer diagnosis,” the Guardian recently reported. “Diamandis’s calculations, based on experimental literature data, give a sense of the size of tumour a ctDNA-based blood test might be able to pick up. His work indicates that with the technology available for analysing ctDNA, tumours would need to be approximately 1cm in diameter or greater to be detected.”

According to Diamandis himself, it is unlikely to find a single fragment of DNA from tumours under that size in the 10ml of blood that is a standard sample.

As he sees things, current tests mainly seem to perform well because they are being applied to people who have already been diagnosed with cancer. “If you go to a real population of asymptomatic individuals, their success rate will be, predictably in my opinion, much less,” he says. “For a [ctDNA-based early detection] blood test – as of today – I am relatively pessimistic.”

In line with Diamandis’s observation, dilution and contamination of ctDNA with normal DNA from dying blood cells have proven especially problematic during recent attempts to use ctDNA for early diagnosed.

As opposed to X-ZELL’s immunocytopathology-based approach, ctDNA-based screening is also affected by ethnicity; meaning current research in the field is limited to a homogenous Caucasian population and has yet to be reciprocated in a more diversified context.

That’s on top of more economical restrictions like high cost, limited scalability and time efficiency, all of which have prompted us to withhold jumping on the DNA bandwagon and instead precede tissue biopsy with tCEC detection.

Solutions have to be grounded in medical systems

With statistics calling for immediate action in the macro, why are existing solutions unable to respond in the micro? To us, the answer is not just technical in nature. For a solution to perform at scale, we believe it must be designed with existing diagnostic decision-making processes in mind.

For a prostate cancer assay, for example, that would mean acknowledging the legacy of PSA testing – it has, after all, led to a drop in mortality – as well as the rise of MRI as an efficient rule-in tool prior to biopsy. Only a solution that will identify the remaining gap in the system and address it directly will find widespread adoption.

That’s why X-ZELL has fine-tuned our tCEC test to serve as a PSA add-on with a very high NPV, allowing physicians to rule out the disease and send home patients with complete peace if mind. Only if we cannot rule out the disease, we recommend going ahead with MRI as a second non-invasive screening tool, and only then should invasive procedures be considered.

Put differently, we understand that any approach to make true, measurable progress towards our goal of zero deaths due to undetected cancer – and, ultimately, contribute to a world where health is something people can expect as a given – must be rooted in a deep understanding of the micro.

Where to from here?

So what’s next? On a macro level, we need to continue pursuing the path paved by the European Parliament in January – to embrace the notion of population-based screening as a viable health management strategy if executed on the basis of sound science and in sync with existing workflows.

In the micro, we need to provide doctors with the same peace of mind a pathologist would, albeit at an early stage in the diagnostic workflow and without exposing patients to invasive procedures.

In our view, doing so requires a cell-based staining approach capable of detecting ultra-rare biomarkers in small blood samples, and analytical equipment that is easy to use in routine laboratory scenarios.

At X-ZELL, we believe we’ve covered both. Powered our very own Cryoimmunostaining™ technology, our tCEC-based assays have the potential to radically change the way we think about early cancer detection and make health accessible to millions around the globe.

Now imagine what else our Cryoimmunostaining™ devices could do for patient health once we make them available to researchers worldwide. Stay tuned.