CRUK Forty years ago, hints of a new component of the immune system caused a stir. As the initial controversy turned into therapeutic promise, the importance of translating this research for the treatment of cancer became very clear. Here, we chart the story of gamma delta T cells from discovery to clinical trials…
“This leads me to one of the greatest occurrences of 2021: the resurrection of the James Bond movie franchise,” says Adrian Hayday, midway through explaining his ground-breaking research in immunology, “it takes me to MI6.”
There are two ways by which a secret intelligence service can detect a threat, Hayday says. “You can either recognise a perpetrator – an identifiable threat – and you track them all the time. Or you can identify atypical activity, even if you don’t know what the origin of the threat is. Today, the prototypical example would be getting your computer hacked.”
In these pandemic years, more and more people are familiar with the idea that B, T and other immune cells deploy a menagerie of mechanisms to recognise and neutralise foreign pathogens such as viruses and bacteria.
But what Hayday has shown over the last forty years – at first very controversially – is that the immune system also contains a population of T cells that execute something akin to the second form of surveillance.
“What these cells are there to do,” Hayday says, “is to recognise when cells are dysregulated; when there is pathology, when there is a disease state that’s developing. And it really doesn’t much matter whether it’s caused by SARS-CoV-2, influenza or cancer.”
But it’s this last source of atypical activity that Hayday now focuses on.
The immune cells that conduct this form of surveillance are a particular class of T cells, called gamma delta T cells. Hayday – a professor of immunobiology at King’s College London, and a Group Leader at the Francis Crick Institute – laid the foundations for the discovery of these cells in the 1980s and has studied their function ever since.
Adrian Hayday is the Kay Glendinning professor in the Department of Immunobiology at King’s College London and a senior group leader at the Francis Crick Institute in the UK.
In 2001, Hayday’s lab published a landmark paper showing that gamma delta T cells help mice resist skin cancer – a finding that pushed him to explore the possibilities these cells might offer oncologists.
Twelve years later, using these cells as a therapy started to become viable when Oliver Nussbaumer, then a postdoc in Hayday’s lab, developed methods for isolating and culturing human gamma delta T cells.
The pair soon partnered with CRUK, Kings and the Francis Crick Institute to form a spin-out company called GammaDelta Therapeutics. And in September 2021, the company initiated a clinical trial in which patients with acute myeloid leukaemia (AML) were dosed with transplanted gamma delta T cells. This was motivated by ongoing unmet clinical needs and by observations that when AML patients are treated with bone marrow transplant, robust engraftment of gamma delta T cells is often associated with the best outcomes.
Hayday believes that the unique functional profile of gamma delta T cells means they will add a vital new medicine to the immunotherapy armoury that has already revolutionised oncology. “Because the gamma deltas have this different way of recognising cancer,” Hayday says, “it’s not just another cell therapy, it potentially transforms the way you do cancer therapy.”
Surveillance system
This story begins in February 1982 with Hayday moving to Boston and to MIT, to work with future Nobel Laureate Susumu Tonegawa. Tonegawa had recently shown that the immune system’s ability to create its staggering diversity of antibodies depended on immunoglobulin genes being rearranged inside B cells. “The next quest,” says Hayday, “was to understand what the T-cell receptor was. How did T cells see foreign infected cells? And what did the genes look like that encode the T-cell receptor?”
This quest was put on a very sound footing when genes for the alpha and beta chains of the T-cell receptor (TCR) were cloned. The proteins encoded by these genes accounted very well for the key pathogen-attacking features of T cells. However, Hayday then cloned a gene that appeared to encode a gamma chain – and nobody knew how to respond.
“That you could just do a molecular biology experiment back then,” he says, “and come up with something that nobody could explain was, to me… Well, I felt very chuffed, I felt very privileged to be in that position. But I also felt sort of bewildered and amazed. And that bewilderment grew when I witnessed the reaction to this.”
Experts across the field belittled the finding. Some said it must be an evolutionary artefact – and most seemed to agree that the gamma chain couldn’t be important. “I think this just rocked the boat too much,” Hayday says.
Undeterred, when he set up his own lab at Yale in 1985, Hayday resolved to figure out what this third receptor chain did.
It soon became apparent that gamma receptor genes were conserved in everything from fish to chickens. “And that just doesn’t happen if something isn’t important,” says Hayday. Then, when a separate lab cloned a TCR delta chain, it became apparent that two types of T cells exist: the very well-studied alpha beta cells and this new gamma delta population.
But then came the next enigma. As Hayday and others sought the function of these cells they found that gamma delta cells failed every classical test for assaying T-cell immunology. “Animals were infected with everything under the sun,” Hayday says, “and these cells seemed to contribute very little; sometimes they didn’t even seem to notice anything was happening!”
While Hayday watched many of his colleagues drift away from this question, he decided that, “what these cells were telling us was to think differently.” And so, he began considering other forms of surveillance.
Gradually, through the 1990s, Hayday started accruing evidence that gamma delta cells detected and dealt with cellular pathology. Then in 2001, his lab published its seminal paper on skin cancer.
The study showed that after being exposed to carcinogens, mouse skin cells expressed a protein that activated receptors on gamma delta T cells. The gamma delta cells destroyed such skin cells. And, critically, when gamma delta T cells were removed from mice, these animals were much more susceptible to skin cancer developing.
To Hayday the implications were clear. He says, however, that in those days, cancer immunotherapy remained in its infancy. And more problematically for researchers seeking funding and recognition for it, many oncologists considered it a lost cause.
Ironically, Nussbaumer says, early efforts to use gamma delta T cells therapeutically didn’t help matters.
There are important differences between mice and humans when it comes to these cells. In mice, most gamma delta cells reside in specific tissues where they survey the cellular neighbourhood. But humans have evolved a second circulating type of gamma delta T cells specialised in recognising infections by bacteria and parasites. The tissue-resident gamma delta T cells that GammaDelta Therapeutics work on are known as Vdelta1+ cells; the circulating human ones are Vdelta2+.
Nussbaumer explains that when researchers first studied human gamma delta T cells they focused on the much more easily accessible blood-borne Vdelta2+ cells – mistakenly assuming they would function in the same way as the tissue-resident gamma delta T cells characterised in mice.
Oliver Nussbaumer is co-founder of GammaDelta Therapeutics.
Initial work on human circulating Vdelta2+ cells went as far as testing them in clinical trials as anticancer therapies – where they failed to produce clear benefits. “Because of the disappointing clinical data,” Nussbaumer says, “this went back to being just a very mouse-focused academic field.”
This mouse field, however, kept suggesting that gamma delta T cells had something important to offer. Hayday’s lab further unravelled the precise mechanisms by which gamma delta cells interacted with compromised cells. Meanwhile, other labs conducted studies showing, in mice, that gamma delta T cells also protect against the development of prostate and colon cancers.
In parallel, clinical studies started to show that the more tumour-infiltrating gamma delta T cells a cancer patient had, the better their outcome.
And equally as important, by this time cancer’s immunotherapy revolution had started. First, check point inhibitors, and then CAR-T therapy obliterated the idea that immunology had nothing to offer oncologists and their patients.
Here, Hayday praises CRUK’s responsiveness to a rapidly shifting landscape. In the early 2010s, when the initial data regarding checkpoint inhibitors was emerging, he witnessed CRUK quickly recognise the significance of immunology and the need to be creative in looking for ways to further harness its potential. “CRUK was not prescriptive about where our cancer research was going and where it needed to go,” he says.
In fact, CRUK asked Hayday to chair a recently formed science review committee – something he says would have been impossible to imagine a decade earlier. Soon after, CRUK launched an immunology grant programme, which, Hayday says “was really helpful in signalling intent and bringing immunologists into the community.”
CRUK funding of Hayday’s lab also meant that they were present when Nussbaumer found a way to harvest large volumes of tissue-resident human gamma delta T cells, and they immediately responded to this development.
Slow, slow, fast
In an academic culture that prizes high-profile publications, Nussbaumer’s appointment was an unusual one. In his previous job, Nussbaumer had helped commercialise research on dendritic cells. He says, “the main reason Adrian and I wanted to work together was to finally make a step forward with human gamma delta T cells and translation. The full point of my postdoc was to translate not to publish.”
On his first day in the lab in April 2013, Nussbaumer met Rick Woolf, a dermatologist taking time out from his medical career to do a PhD with Hayday. Using his clinical connections, Woolf could provide a steady supply of skin samples, and together he and Nussbaumer explored ways of extracting and accumulating human gamma delta T cells.
“Nobody ever knew how to grow these cells,” Nussbaumer says. “And we didn’t know either so we just tried the kitchen sink approach. Everything that might somehow, in theory, stimulate T cell growth, you name it we tried it.”
Unlike traditional isolation techniques which digest and homogenise tissue, Nussbaumer and Woolf forced the cells to migrate out of skin sections. Then they established conditions in which the cells would grow.
To their surprise, the gamma delta T cells they wanted – Vdelta1+ cells – grew in the lab’s control conditions. “We basically stumbled over a way of growing the cells, in the one condition we didn’t anticipate them to grow at all. Once they are out of the skin, you just feed them cytokines and they keep growing, growing, growing,” Nussbaumer says, “so, we suddenly had a method to expand the cells into the billions.”
The central aspects of this technique were established within six months of Nussbaumer joining the lab, and within a year it was mature enough to call a meeting with CRUK. This happened on 14 May 2014 – Raj Mehta, the CRUK representative, preserved his notes in a pdf, so certain was he that something significant was afoot.
Mehta was Cancer Research Technology’s (CRT) Business Manager at the CRUK London Research Institute, where Hayday had moved part of his lab just five years earlier. Mehta had, Hayday says, “been keeping an eagle eye on us”.
Excited by what they had shown him, Mehta immediately helped Hayday and Nussbaumer file two patents covering the cell production protocol. Then he guided the two researchers through the next stage of commercialisation.
“We were a bit naïve,” says Nussbaumer, “we had these two items of IP and the idea was, ‘let’s just license them out to a pharma company, and they can develop it.’ The vision for something bigger was CRT’s. It was Raj who said, ‘No, this is not something to license, let’s do a start-up.’”
GammaDelta Therapeutics was at first a virtual company, formed in 2016 with enough money to hire two postdocs who worked in Hayday’s lab. But soon CRT drew up a list of potential investors who might offer a way to grow the company.
The sales pitch focused on how sensitively gamma delta T cells detect cancerous host cells – much more so than alpha beta T cells do – and how gamma delta cells offered an entirely new way of doing cell therapy in cancer. Because these cells recognise diseased cells independently of the major histocompatibility system, cells taken from a single donor can in theory be given safely to any suitable recipient. “This was a potentially game changing point,” says Hayday, “because we can have an off-the-shelf, on-demand cell therapy for cancer.”
“We showed all the mouse data, which is very convincing. Then showed the clinical data,” says Nussbaumer. “Then, the only problem was that nobody could grow these cells, otherwise we would have used them long ago – a problem we overcame.”
Success wasn’t instant. For about a year, Hayday says he, Nussbaumer and Mehta “wore out a lot of shoe leather” visiting companies. “We got warm words, but warm words don’t get the job done. But then we captured the interest of Peter Goodfellow who had been Senior Vice President at GSK and was now a consulting advisor to Abingworth.”
Abingworth is a transatlantic venture capitalist company that invests in bioscience, and Goodfellow – now chair of the board of GammaDelta Therapeutics – championed this proposal. The company gave some seed funding and shepherded the company through its next phase.
When Abingworth’s initial targets were met ahead of schedule, the company set up a meeting with Takeda. The Japanese pharmaceutical company had strong links to emerging cell therapies – around which there was now growing excitement and anticipation – and they were quickly convinced by GammaDelta Therapeutics’ vision.
So much so that in May 2017 Takeda arranged an investment package whereby they would provide up to $100 million to fund the start-up for up to five years in exchange for having first option to buy GammaDelta Therapeutics should they want to. “They invested a very significant amount of money,” says Hayday, “which essentially enabled the company to run without having to continually prepare presentations for subsequent rounds of financing.”
“I think people really undervalue how important that is,” he continues. “It meant we could just focus. And I think that’s why, in what I believe is really an incredibly short time, we have cells in the clinic.”
GammaDelta Therapeutics
When the company was formed, both Nussbaumer and Hayday had to decide what their relationship with GammaDelta Therapeutics would be. For Nussbaumer, this was simple – he soon joined as a full-time staff member, becoming Head of Cell Research in April 2017. Today he is Vice President of Immunology.
For Hayday, it was more complicated. The company’s backers told him they’d be happy for him to join full-time. But, he says, “that’s fundamentally not who I am. I’m a basic scientist. I had a lab full of postdocs. And so, I didn’t really want to do that.”
They also gave him the option to walk away, albeit everyone agreed this would look suspect, and besides, Hayday’s life’s work was going into this company.
He therefore sought a middle ground, mindful that he didn’t want to be caught between his commercial and academic roles, unable to thrive in either. “It’s extremely tricky,” he says, and he believes no one-size-fits-all solution exists for academics founding companies. Among his friends and colleagues, he’s seen various distinct arrangements reached.
In the end, Hayday assumed two roles – he is a board member, and he is a scientific consultant. He routinely reviews what the company is doing from a scientific perspective, and with his employer’s consent, he shares relevant work that his lab is doing. Hayday has, however, no executive power to officially alter the company’s scientific agenda. “It’s been a learning experience,” he says. “You have to moderate your expectations downwards for some things, and very happily upwards for other things.”
Between the company’s formation and the instigation of clinical trials, they invested heavily in honing their cell production techniques, including meeting the non-trivial matter of making the cells cryopreservable. Hayday notes that enormous amounts of effort have been expended by those within the company, from ground level up to senior management, so that the initial scientific data could be translated into a pharmaceutical product fit for treating patients. Indeed, as just one part of those efforts, GammaDelta Therapeutics acquired a second company, founded by another former Hayday postdoc, Bruno Silva-Santos, giving them more options for harvesting and growing cells.
After beginning life in a bioincubator space in North London, the company has since moved into purpose-built labs on the White City campus, the BBC’s former headquarters. Their staff now number about 65.
The current trial using gamma delta T cells to treat patients with AML only marks the beginning of GammaDelta Therapeutics’ ambitions. While Nussbaumer and Hayday hope that naked, unaltered cells will clinically benefit patients, the company is exploring multiple ways to maximise the cells’ potential. Examples include genetically engineering gamma delta cells so that they express further receptors for detecting cancerous cells. The hope is to increase their potency, while still maintaining the cells’ exquisite ability to distinguish between healthy and compromised cells.
Given that gamma delta cells reside in tissues, it is also hoped that they will offer new possibilities for targeting solid tumours, and multiple possible strategies for genetically engineering the cells to increase their activity at such sites are being explored.
The company also investigated activating antibodies that might be given to cancer patients to boost the activity of their own gamma delta T cells. This has led to a second spin out company, Adaptate, so that the respective companies could each have a single focus.
Altogether, things have gone so well that Takeda recently exercised its right to buy both GammaDelta Therapeutics and Adaptate. For GammaDelta, Takeda opted to do so with a year left to run on its initial five-year build-to-buy timeline. “We got into the clinic, and Takeda are as excited as they were four and a half years ago. Now they want to do it in house; to bring it into Takeda to accelerate it because they have a massive number of staff and state of the art facilities dedicated to cell therapy.”
With other clinical trials under consideration, the company must now wait to see how the first-in-human data pan out. There should be results within the next couple of years.
“I’m very excited,” says Hayday, “because I never really quite thought this would happen, though I always hoped it would.”