For years, CD25 was written off as a cancer drug target. But after Sergio Quezada’s team discovered a new way to target this receptor, a whirlwind process of drug discovery ensued. In 2008, working as a postdoc, Sergio Quezada published a paper that helped consign CD25 – a receptor found primarily on immune cells – to the large scrapheap of “molecules-that-scientists-formerly-considered-exciting-targets-for-cancer-therapy”.
But then, in 2010, the picture began to change. New data from cancer immunotherapy studies Quezada had been running in his newly established lab together with his colleague Karl Peggs, caused them to reconsider CD25. It looked like it hadn’t been the target that was wrong… it had been the antibody.
Fast forward to 2021 and Quezada is just about to address the meeting of the American Association of Cancer Research to describe promising early results of how an anti-CD25 antibody can indeed trigger an immune response that causes tumours to completely disappear in mouse models.
CD25’s relaunch as a drug target was owed to experiments – done in Quezada’s and Peggs’s labs at the UCL Cancer Institute and supported by Cancer Research UK (CRUK) – that demonstrated the importance of a sub-set of T cells known as regulatory T cells in inhibiting immune responses to cancer cells. Quezada worked with CRUK to secure patents on the approach. Then, in 2016, with CRUK’s help, he partnered with a small UK biotech called Tusk Therapeutics to develop a drug.
In an early meeting with Tusk, Quezada was asked if the antibody his team had used was the best he could provide? Taken aback, he replied: “We spent 10 years figuring out this thing, and now you want something better?
But this conversation sparked an insight that changed everything, ultimately leading to a drug that was instrumental in Roche paying up to $798 million to acquire Tusk in 2018. Reflecting on the work with Tusk, Quezada says, “It was a delight – one of the best collaborations I’ve ever had.”
Quezada’s early work on CD25 was conducted in Jim Allison’s lab at Memorial Sloan-Kettering Cancer Centre in New York. The immunotherapy revolution unfolding there was founded on the fact that the human immune system normally destroys cancerous cells, but that as certain tumours grow and evolve, they start to evade immune surveillance.
Allison had shown how, as a tumour develops, mechanisms emerge which suppress a critical population of T cells, known as effectors, that normally recognise cancer cells and tag them for destruction. Some of the signals that inhibit T effectors in tumours act at checkpoint receptors – receptors that ordinarily function to keep any immune response proportionate to the need for them. And Allison’s demonstration that blocking these checkpoint receptors disinhibited T effectors, allowing them to destroy patients’ tumours, won him a share of a Nobel Prize.
Allison’s focus was T effector cells, their interaction with cancer cells and how this is regulated by checkpoint receptors. But Quezada was interested in a third player: regulatory T cells or Tregs. These T cells function to suppress T effectors and thus regulate immune responses. Quezada asked whether Tregs inhibiting T effectors within tumours are also critical for cancer cells escaping the immune system? Gradually, he convinced himself and Allison that this was an essential piece of the puzzle.
But an equally important legacy of his time in the Allison lab, was Quezada witnessing first-hand how the clinical success of checkpoint inhibitors was achieved by basic researchers and clinicians working in constant dialogue. “That’s when I started seeing the power of taking basic research and being very smart on how you analyse its impact as it gets into the clinic,” he says. “I said, ‘This is exactly what I want to be doing. I want to be working at this interface’.”
At this point, Karl Peggs, a clinical fellow with whom Quezada had worked with in Jim Allison’s New York lab, was instrumental in recruiting him to UCL. Peggs had already moved to London and he told Quezada that if he moved to UCL, he could plug a gap between clinical trials and basic immunology research.
A grant from CRUK was instrumental in securing the position. “We first supported Sergio through a CRUK career development fellowship back in 2010,” says Matt Kaiser, Head of Careers and Discovery Research at CRUK. “This allowed him to bring his expertise to the UK and establish his own research group.”
Yet, despite his and CRUK’s translational ambitions, Quezada didn’t arrive at UCL with a specific drug in mind. “I don’t think that’s how it works,” he says. “These things are organic. It’s like a little plant, they emerge.”
A seed, however, had been planted in New York with the Treg work. The checkpoint inhibitors that had entered the clinic were thought to act by directly disinhibiting T effectors. But Quezada’s group – controversially – found evidence that these drugs could also deplete Tregs in tumours and that this was a vital part of their action.
This reignited interest in CD25 because – unlike checkpoint receptors – it is expressed abundantly on Tregs and only at low levels on T effectors. Designed the right way, he and his group postulated, anti-CD25 antibodies might offer a way to powerfully and selectively deplete Tregs and liberate T effectors to attack cancer cells. Then came the moment the team had been dreaming of – they found their newly designed antibody caused a stronger immune response against the cells it bound to – which in turn caused tumours to shrink. “That was kind of the eureka!” Quezada says.