Author: Britt Christian

Two years after Neil Armstrong walked on the Moon, US president Richard Nixon declared a new frontier in American scientific conquest. The target was one of humankind’s biggest killers: cancer. “The same kind of concentrated effort that split the atom, and took man to the Moon, should be turned toward conquering this dread disease,” Nixon declared on December 23, 1971 as he signed the US’s inaugural National Cancer Act. The aim was unequivocal – nothing short of a cure across the gamut of cancers.

Politicians love a lofty goal, but the enemy at the time was barely understood, let alone close to being conquered. Fifty three years on, enormous strides have been made in understanding cancer biology and tumour microenvironments – yet for all of our scientific knowledge, combating the spread of malignant tumours in some of our most deadly cancers is still a losing battle, with the errant cells always one step ahead in their ability to evade both immune fightback and drug weaponry. The fight has been infinitely harder than Nixon imagined.

Cancer is still the second-biggest killer worldwide; three out of every ten deaths in Australia are attributable to it. No other disease touches everyone’s lives in the way cancer does. Almost everyone has a friend or relative who has battled the disease, or in the worst case lost their life to it. Sometimes, it’s the treatment that kills people. Because while the development of immunotherapies and targeted treatments stretches back at least 70 years, the science has been inchingly slow at getting these therapies into the clinic, leaving the blunt tools of chemotherapy and radiotherapy – which often have severe side effects – as the standard treatments for many. So far, monoclonal antibody treatments and other immunotherapies have revolutionised the treatment of only a small suite of cancers.

Yet that may be on the cusp of changing, with a groundbreaking clinical trial proving this year that the majority of melanoma patients whose cancer has spread to the brain can be “cured” when given combination immunotherapy as a first-line treatment. The trial, led by scientists at Melanoma Institute Australia, has presented data that establishes long-term disease control is possible for advanced melanoma patients when given two checkpoint inhibitor immunotherapy drugs, nivolumab and ipilimumab, in combination. The approach is now likely to be replicated in clinical trials across a number of cancers including lung cancer, kidney cancer, head and neck cancer, bladder cancer and triple negative breast cancer.

At the same time, renowned pathologist Professor Richard Scolyer, who was diagnosed with the deadly brain cancer glioblastoma almost two years ago, has been able to extend his life beyond all expectations through a novel personalised “vaccine” that works by activating the immune system and instructing T-cells to kill tumour cells. Scolyer is currently recovering from brain surgery after scans revealed a recurrence in his cancer, but his relative longevity has provided hope for future sufferers as science’s war on cancer occurs across multiple fronts. It’s what federal health minister Mark Butler called a “turbocharged period” of discovery on cancer therapies, after announcing public funding for the first pan-tumour pharmaceutical – Vitrakvi – that has been described as a likely game-changer in precision oncology.

Meanwhile, the combination of technologies such as gene editing has driven advances in new types of immunotherapies, combined with advanced imaging techniques that provide unprecedented insight into immune cells’ responses to cancers. It’s opening up what is set to be the most exciting era yet in effective therapies. “I think we’re looking at a future in which cancer becomes a chronic disease, where we can outlive it,” says Associate Professor Arutha Kulasinghe from the University of Queensland. “I think that’s where we are moving towards. Cancer shouldn’t be a death sentence.”

“The reality is, cancer is so complex. It’s so devious,” says Kerry Strydom, CEO of the Australian Cancer Research Foundation. “It’s not one disease. So the complexity in terms of the treatments – in terms of finding something that even works for a while, and then it stops working as the cancer finds its own way to resist the treatment – is almost overwhelming.

“But innovation is going to cut through all of this. That is what’s going to be able to pull all of this data, all of this research, all of these pieces together, to cut through to an end result. From a technology perspective, this is a moment in time when some of these ideas that researchers have been working on for decades are able to be investigated further. It’s transformational. There is huge potential ahead.”

Few people are watching developments in innovation as closely as Sydney mother-of-two Caitlin Delaney. A scientist by background, she was diagnosed with Stage IV ovarian cancer eight years ago. Her type of cancer – clear cell ovarian cancer – is rare and particularly aggressive. She is only alive today because of her determination to access cutting-edge therapies as a result of her own research. Initially, standard treatment of surgery and chemotherapy was successful, but after two years her cancer recurred. “I was told that standard treatments wouldn’t work for me any more,” Delaney says. “Of course this was very concerning. But that probably did me a favour, because it made me look outside of the hospitals and made me advocate for myself even more. I realised I had to find out who the global experts in my type of ovarian cancer are, what the latest science in the labs is, and how I can access that.”

Delaney had previously pushed for genetic testing, and learned that her tumour had mutations that could be targeted. She then accessed an immunotherapy drug combination off-label, at great expense, that kept her stable for two and a half years. “It made me realise there is hope, I’ve just got to look for the emerging science,” she says.

Since that immunotherapy drug combination stopped working for her, and after more treatments and an aborted clinical trial attempt, her cancer has progressed, leaving her in the position of having to crowdfund further treatment. Now, Delaney is watching the rise of a very promising new form of immunotherapy that re-engineers a patient’s own T-cells, the white blood cells that help the immune system fight off disease. Known as Chimeric Antigen Receptor T-cell therapy, or CAR T-cell therapy for short, it has proven highly effective for blood cancers, but has not yet been able to make the leap to treating solid tumours such as ovarian cancer.

But the eagle-eyed Delaney, who has a degree in biotechnology and who’d signed up to the newsletters and followed market announcements of various biotechs in the cancer space, began to see talk of another type of CAR therapy – this one involving engineered natural killer cells. “I could see there was a lot of money being raised. I had the feeling that this is going be the next thing,” Delaney says. “I just don’t know if I’m going be alive to witness it.”

Inside a small row of bioreactors in a Melbourne laboratory, stem cells derived from umbilical cord blood are forming into three-dimensional groups in a special solution, in a process that mimics the development of one of the most powerful of the body’s immune cells: natural killer cells. NK-cells are lymphocytes of the innate immune system sometimes known as the “tumour killers” that are critical in
detecting and controlling early signs of cancer.

Holding forth in this east Melbourne lab is stem cell biologist Alan Trounson, who decades ago led an Australian team that discovered human embryonic stem cells, and who between 2007 and 2014 headed up the Californian Institute for Regenerative Medicine, a $3 billion stem cell agency that was a world leader in facilitating the translation of stem cell discoveries into clinical therapies. Trounson, an Emeritus Professor Monash University and Distinguished Scientist at the Hudson Institute for Medical Research is also a pioneer of human in vitro fertilisation. There could be few scientists better qualified to utilise the power of stem cell technologies as the basis for engineering an immune cell uniquely primed to conquer one of the deadliest of cancers.

“I’m about research that can actually target something that is a problem,” says Professor Trounson. “I see problems as things that we could possibly solve if we apply the right kind of science to it. We wanted to go after the toughest cancer, the one that hasn’t got a treatment. We chose ovarian cancer. It could have been something else, but ovarian cancer has few therapeutic options. As a scientist, you’re looking for opportunities to make a difference to problems that could be solved using skills and innovation. There’s an opportunity of using stem cells to control ovarian cancer.”

Professor Trounson and his team at the biotechnology company known as Cartherics that he has founded to develop cell immune therapies are engineering natural killer cells that will be super-primed to kill ovarian tumour cells. They’re creating what are known as CAR-NK cells – a type of immune cell engineered to express a chimeric antigen receptor, a type of synthetic receptor for proteins known as antigens that can direct the functioning of immune cells. The CAR-NK cells are specifically designed to target and destroy cancer cells with high efficacy. They contain activating receptors that recognise molecules that are expressed on the surface of cancer cells and virally infected cells which ‘switch on’ the NK cell to kill. They also contain inhibitory receptors that act as a check on NK cell killing. Cancer cells are clever, and often put out signals that activate these inhibitory genes on the NK cell so that it no longer performs its killing function. However, the process of gene editing involved in engineering CAR-NK cells to “knock out” these inhibitory receptors so the immune cells are not blocked from carrying out their function.

“These cells that we make up are even more aggressive at killing tumour cells than the body’s own natural killer cells because they don’t have some of the natural inhibitors that an adult NK cell has, so they just kill dramatically quickly,” Trounson says. “And so we want to deliver these very aggressive natural killer cells directly into the pelvic cavity where the ovarian cancer is. We don’t want to drop them into the blood. We want to put them where the cancer is.”

It is early days for Professor Trounson’s work, but animal studies have provided enough confidence for the US Food and Drug Administration to provide the guidance for an IND to enable a clinical trial which is set to begin in Australia late this year or early next year. There is hope that the emergence of this next wave of cancer immunotherapy – which follows the stunning success in blood cancer of a similar type of therapy known as CAR-T cell therapy – is likely to open up promising treatment pathways for tumours which have long had terrible prognoses. If it proves successful, CAR-NK therapy could have application across a wide spectrum of cancers, including gastric, colorectal, prostate and pancreatic cancers.

At the same time, efforts are underway to extend the application of CAR-T cell therapies to solid tumours. The technology is similar to CAR-NK therapy but rather than being an off-the-shelf product, involves gene editing and re-engineering patients’ own t-cells to fight cancer. It has had success rates of up to 90 per cent in treating blood cancers so far, but has been associated with significant side effects including immune overactivation known as “cytokine storm”, and also neurotoxicity.

The Peter Mac Cancer Centre in Melbourne is at the forefront of adapting CAR-T cell therapies to solid tumours, primarily utilising CRISPR gene editing tools. “There are many advances that are starting to show promise,” says Associate Professor Paul Beavis, immunologist at the Peter MacCallum Cancer Centre. “The field is actually flooded with innovative technologies. So there’s one thousand and one things you can try. The question really is how do people rank them, and which are the ones that are the best to try next?

“My kind of selling point as an immunologist is that because cancers arise from mutations, there’s always the potential for the immune system to recognise these cells as being different. And so as we become more sophisticated in our tools, I think we’ll be able to unlock that.” At the same time as this new wave of cancer immunology research is unfolding, a revolution in understanding of cell biology is developing that has the potential in the future to personalise cancer treatment to a remarkable extent.

Late last year, the Human Cell Atlas project released details of what it described as an unprecedented feat of “human cartography” that outlined cell maps of the human body with a level of detail never before seen. The project has not only described a host of new cell types, but has also revealed exactly how the body’s cells communicate with one another – a mechanism that is particularly important for cancer researchers crafting therapies that harness the body’s own immune response. This kind of three-dimensional digital cell mapping requires advanced imaging techniques and utilises an emerging field of pathology known as spatial biology.

“This will be truly transformative for cancer medicine,” says Kulasinghe. “With traditional approaches, and even when you do genomic testing, you get these sort of bulk profiles of the tissue, but we have no appreciation for where all of the different cells came from in the context of the tissue. So even in CAR-NK or T-cell therapies, there’s no appreciation for what immune cells are actually doing. Now, we have context for every cell within the organ of disease. So we know where the T-cells are. We know where the NK cells are. We know where the tumour cells are. Are they knocking on the door of the cancer cells? Are they at that interface where the tumour cells are interacting with the immune cells? Or are they in the middle of the tumour, for example?

“With these new cell mapping techniques you’ve taken that story of biology and turned it into a digital image of that patient’s tumour. And so we can ask the question, you know, do the NK cells or the T-cells or the macrophages outside the tumour, how do they compare to the immune cells within the tumour? And then you start to learn things like cell patterning. So what are the patterns associated with patients that respond to therapy? What are the patterns associated with patients that don’t respond to therapy? Are the right types of immune cells recognising the tumour? Can we see it? Do we know that it’s engaging all of the tumour? Do we know areas in that ‐ tumour that have no immune cells?

“And so we’re getting more appreciation for where these immune cells are, and the role of those immune cells. Are they exhausted? Are they active? Are they killing the tumour cells? We’re no longer acting off assumptions. We know exactly where these cells are – and that seems to be the transformative piece now in immunology, in tissue mapping, because where these cells are in the tissue is critical, and we’ve never had the tools to be able to look at them before.

“A tumour is always actively trying to mask itself from the immune system, trying to cloak itself. So in the future we’ll have much greater insight into how we can de-cloak these tumour cells, expose immune cells to the tumour and the tumour microenvironment, and then let your body go and kill those [cancerous] cells or turn them off.”

It is likely, as science continues its battle against a constantly evolving enemy, that greater understanding of how to harness the strength of the body’s own immune system will be the most powerful weapon in clinicians’ armoury in treating cancer. Splitting the atom and setting foot on the Moon were astonishing feats of science. Perhaps no one could have predicted combating cancer would turn out to be so much harder.

Article sourced from The Australian website here.