Cancer research leading to a treatment revolution

On Waterloo Quadrant sits the High Court. Today, as in most weekdays, some trials of great significance are under way. Just across the road, more trials are taking place. Here at the Thomas Building is a research centre focused on immune therapy – one of the most significant cancer treatment developments in the past decade – which Professor Rod Dunbar drives.

Rod is the director of the Maurice Wilkins Centre, a position he's held for almost ten years, co-ordinating research across New Zealand in human therapeutics.

After completing a medical degree and a PhD, Rod spent six years as a post-doctoral research fellow in human immunology at the University of Oxford before returning to New Zealand in 2002. He has specialised in immune therapy since his Oxford days.

Rod spoke to Ingenio ten years ago about his work in immune therapy: identifying and purifying the particular T-cells in the blood that have the capacity to recognise and kill cancer cells. Those cells, once stimulated and fed with the right nutrients, can keep dividing to produce an army of identical cells, all with the same capacity to attack and kill cancer cells while leaving normal cells alone.

Back then, Rod described immune therapy as "the next frontier" in cancer treatment. Now, he says, it's the "big revolution" in cancer care. As an example, he cites his work with Dame Margaret Brimble – another Maurice Wilkins Centre principal investigator. Together, they have developed innovative chemical technology to generate cancer vaccines. As reported in Ingenio Autumn 2018, this work is being translated for clinical use by the spinout company SapVax, which is developing a pipeline of products for the treatment of different cancers.

To illustrate the work to date, we tour Rod's research facility. First up, there's a new arrival to view: a machine used to analyse different cells within tissues, including cancer tissues. The significance of its arrival is marked in the fact Rod's colleague, Dr Anna Brooks, who leads the Auckland Cytometry facility, knows the exact date of its arrival: "7 January", she enthuses.

Explains Rod: "What Anna's done with our flow cytometry facility is develop cutting-edge tools that are not only being used in our research, but are also being used by companies from around the world in their clinical trials in Auckland.

"Every single dot you see on the screen is a particular cell … one collection of dots is T-cells that can kill cancer cells, and we can separate these cells out and make them multiply."

Deeper into the lab is a development that takes cell culture a significant step further. It's a clinical grade cell culture suite that completely isolates the cells inside a machine sealed off from the room outside. Inside that space are filters, such as those seen in operating theatres, that clean the air so there are no infectious particles. This guarantees sterility, and enables cells to be grown safely for use in the clinic, says Rod. The lab is almost ready to produce T-cells for patient treatment, with the first clinical trial planned for 2020.

"We take a sample of a patient's blood and we stimulate it in ways that grow the cancer-killing T-cells. Because they have been confined inside that sterile environment, we will be able to inject them safely back into the patient."

In other words: custom-making cells to target an individual cancer patient's tumour.

That wouldn't be possible in a lab other than one of this type, which uses an internationally recognised quality-control system that ensures therapeutic products are produced consistently and safely.

And nor would the unit be functioning were it not for the efforts of one particular philanthropist, who chose anonymity but whose largesse enabled the development of the cell therapy unit's processes and protocols.

"The scale of philanthropy that New Zealanders are now contributing to the University is incredible," says Rod. "As researchers, we are so grateful – these gifts make an enormous difference in lifting our ambitions and enabling us to reach for goals that would simply be unachievable through our public science funding."

So how does the kind of cell therapy Rod's team is developing relate to the ongoing immune therapy "revolution"?

Rod notes that some forms of immune therapy are now first-line therapy for patients with some types of advanced cancer – the classic cases being melanoma and lung cancer patients who had "a terrible prognosis" up until very recently.

"Even in patients with the most dreadful disease, a modest percentage of them are now surviving for very long periods after immune therapy – in fact, they are probably cured. "That's a really impressive clinical signal – not just a result from a lab dish or an animal model – so it gives us hope that all cancer could eventually be brought under control by adding in immune therapy to a combination of conventional therapies such as surgery, chemotherapy, and radiotherapy.

"In fact, I can now tell my students with some confidence that cancer will be far less of a problem for their generation than it was for their parents' generation. At the rate things are moving, more and more cancers will be brought under control over the next two decades."

But major challenges remain. Immune therapies can only cure patients if their T-cells can attack and kill every single cancer in the body. So, one of the challenges is to understand exactly which molecules inside the cancer cells make them most vulnerable to T-cell attack – and least able to escape that attack.

Rod likes to draw an analogy with the iconic Cerebos salt cellar, which bears a picture of a boy chasing a bird. "If that kid's eventually going to grab the tail feathers of the chicken, the chicken is going to ditch the feathers and run off."

Cancer cells have the same capability – they can switch off molecules that make them vulnerable to T-cell attack. Working with bioinformatics expert Dr Klaus Lehnert, Rod's team is trying to define molecules within tumours that can be recognised by T-cells, but can't be discarded like tail feathers.

"And then, of course, once we grow T-cells that recognise those molecules, we'll soon be able to infuse them into patients and test whether they can really control their cancer."

Some 20 years ago, he wrote his first paper showing that cancer-killing T-cells could be purified directly from patient blood. "But even when I was in Oxford, I didn't have the capability to test whether they'd be useful in patient care, since Oxford lacked a cell therapy facility. Now we've built one at the University of Auckland, and we can directly test whether our new T-cell culture methods will benefit patients – informed by all the incredible science that's happened since."

Dr Paula Barlow was a student who completed her medical degree in 2008. She has gone on to specialise in medical oncology, and until recently was a research fellow at the Auckland Cancer Trials Centre. When she was at medical school, the mainstays of treatment were chemotherapy, surgery and radiotherapy. There was no talk of immune therapy.

Since then, she has witnessed a rapid change in the approach to cancer treatment.

"One of the most significant changes we've seen is the introduction of more targeted therapies, such as tyrosine-kinase inhibitors and antibody treatments," she says. "These drugs more specifically target cancer cells, often resulting in better treatment outcomes with fewer side effects compared to traditional chemotherapy."

More recently came the addition of immune therapy. "This is where there's been an explosion of information within the past few years. There have been very exciting developments – not only immune therapy, but also combinations of immune therapy with other traditional treatments such as chemotherapy."

The combinations often seem to be more effective than either agent by itself. "With each step along the way, it's another addition to our arsenal of weapons against cancer," says Paula.

Again, philanthropy has played a key role in enabling more work to be done. Driven by Dr Sanjeev Deva – the centre's medical director – the Auckland Cancer Trials Centre was funded by an anonymous donor. Opened in 2017, it runs as a partnership between the University's Faculty of Medical and Health Sciences and the Auckland District Health Board. In its first year of operation, it saw more than 80 patients with advanced cancer through its doors, all of them involved in early phase trials of novel anti-cancer therapies.

Says Paula: "It's been a really inspiring time in terms of developing that research base at the hospital. Importantly, there has been more clinician-scientist collaboration through this work as well."

She developed an interest in medical oncology during her final year at medical school and says that one of the aspects that drew her to it was that it was such a rapidly changing field. "I imagine the way we treat patients at the end of my career will be extremely different from the way we treated patients at the start of my career, and I'm already seeing some of that change, which is remarkable."

Some of that change comes from Professor Cristin Print's area of research – genomics and bioinformatics. It's the analysis of gene sequences and how genes are used in health and disease. After his PhD in immunology, he spent four years in Melbourne, then six at Cambridge.

He and his Cambridge colleagues published their first research paper using genomics in 2003 – at that stage their analysis used a second-hand robot to spot microscopic amounts of DNA onto small pieces of nylon paper. While these methods were groundbreaking at the time, today Cristin and his Auckland colleagues Dr Ben Lawrence, Dr Cherie Blenkiron and Dr Annette Lasham use DNA sequencing machines to "read" hundreds of millions of DNA sequences from a patient's cancer. Working with bioinformaticians Peter Tsai, Dr Ben Curran and Dr Nicholas Knowlton, Cristin's group use high-performance computers and Artificial Intelligence to identify personalised therapies and predict individual patient prognoses. PhD student Tamsin Robb used those methods to analyse the genetic evolution of more than 20 metastatic tumours in one patient.

Says Cristin: "Our work has shown that in some tumours, changes in the number of copies of whole chromosomes may be the main driver of tumour development, rather than mutations in individual genes."

Working with PhD student Sandra Fitzgerald, and cancer clinicians Dr Rosalie Stephens and Dr Jon Mathy, he's recently begun to successfully sequence the cancer DNA that leaks out of tumours into the blood of patients. "This allows you to monitor a tumour, its specific mutations and its genetic evolution over time using simple blood tests in the community, rather than patients needing to go through tumour biopsies in hospital. Our vision is for all cancer patients to receive personalised therapy based on genomic testing of their blood samples."

The changing shape of cancer treatment is something Distinguished Professor Bill Denny knows all too well.

Bill, a director of the Auckland Cancer Society Research Centre and co-founding scientist of Proacta Therapeutics, has been designing cancer drugs for 42 years. The Auckland- and Oxford-trained medicinal chemist can map the advances – and challenges – since he first stepped into the Auckland lab after he left a promising pharma offer in London in 1972. Back then, New Zealand's 10-year cancer survival rate after diagnosis was 24 percent. By 2014, the rate had increased to 57 percent, according to Ministry of Health data. That's come through a combination of factors: better lifestyles, better screening and earlier treatment – via surgery, radiotherapy and new drugs.

"But it begs the immediate question of how can we improve things further," says Bill. He enjoys international recognition: his awards include the Rutherford Medal of the Royal Society of New Zealand, the Adrien Albert Medal of the UK Royal Society of Chemistry, the American Chemical Society Medicinal Chemistry Award and an Officer of the New Zealand Order of Merit for services to cancer research. His colleagues and associates just call him Bill.

Professor Rod Dunbar goes further than that to describe Bill. "He's been peerless in his ability to keep an extremely large team of world-class scientists going for decades. If he was in the Olympics, he would be a serial gold-medal winner and, frankly, we would have knighted him years ago for his level of performance." To date, the centre Bill heads has taken 15 new drugs to clinical trials in New Zealand and around the world.

When Bill first returned to his homeland from his post-graduate studies, cancer treatment was more of a one-size-fits-all approach. The drugs used targeted DNA and were generally more toxic than they are now. They did not benefit all patients.

Now, therapies are much more focused on individuals, says Bill. "The real difference between then and now is that now we know every cancer is different for each person, and changes over time."

Cancer technology has moved on a great deal since Ingenio did its last major feature on the subject, ten years ago. Consequently, Bill and a wide range of collaborators – scientists, clinicians and outside commercial companies – now understand the "staggering" complexity of a human cell and the proteins inside it. "It's only when we get to the atomic level that we see the unique differences between proteins, and target them," he says.

The centre he heads has three key areas of research: drugs to control cancer cell signalling; drugs targeting hypoxic (oxygen-starved) cancer cells and drugs to boost the body's immune system. The steps they have taken with drugs to control cancer cell signalling have seen them establish an acrylamide "lock" unit, which inhibits signalling pathways in cancer cells. Since its inception in 2000, 12 such drugs have been approved – all of them applying this concept.

Hypoxic tumour cells are difficult to kill with conventional drugs. These cells can also reoxygenate and repopulate a cancer after treatment. However, Bill and his team have moved to fight them from within by developing hypoxia-activated drugs that contain an oxygen sensor that keeps the drugs non-toxic until they reach the remote oxygen-starved cells.

"They then turn on to become toxic and the toxic form redistributes throughout the cancer," says Bill.

Three drugs have reached clinical trial in this area.

And then there's the immune system, "our frontline defence against cancers," says Bill. He says not so long ago the system was so complicated that "we couldn't even contemplate how we would affect that". That has all changed dramatically in the past decade.

One programme developed by Bill and his team subverts the immune system's response to cancer by using a drug to recruit a patient's own immune cells and then start generating growth factors. These can cause cells to be stimulated and to grow, shutting down the protein secreted by cancers. Immune therapy, increasingly based on each individual patient's genetics, is the next big thing, he says.

All this work costs money. Bill says people are always commenting on the "horrendous" costs of new drugs.

"The dilemma we have is that because of the focus on drugs and new classes of drugs, the cost of them is going up. But at the same time as we subdivide cancers into smaller blocks, the patient population becomes smaller, so the cost of treatment soars."

The government is unable to fund everything, he says, and costs truly have risen. The role of philanthropy in developing drugs to go to trial and beyond is equally huge. While the Cancer Society provides substantial funding to the Auckland Cancer Research Centre, Bill and his colleagues still have to find a considerable amount themselves.

"The Cancer Society contribution is absolutely critical," says Bill. "But beyond that, the Centre still has senior staff at associate professor level who have to write their own grant applications." The Research Centre wants to see cancer survival rates increased to 75 percent within the next decade. It's a goal they're working towards with many other researchers around the University. For example, Auckland Bioengineering Institute experts have developed computerised models to help detect and track the path of breast cancer – models that are shared with clinicians to improve treatment. Cristin Print, who also chairs the scientific advisory board of the Auckland Regional Tissue Bank, says there's another important group to acknowledge in the fast-moving realm of cancer research.

"Tissue banks hold patient registers and tumour tissues bravely donated by consenting patients – they're the core of genomic cancer research."

The importance of the work by University of Auckland cancer researchers is profound for those with cancer, such as young Lucca, who features in the video above with her mum, Jordanna. The development of new drugs is key to staying abreast of the latest treatments.