CAR T-cell therapies hold the promise of curing solid tumour cancers. Dr John Maher, Chief Scientific Officer of Leucid Bio, explains how his biotech is developing the technology.
Forward: features are independent pieces written for Mewburn Ellis discussing and celebrating the best of innovation and exploration from the scientific and entrepreneurial worlds.
‘Stellar’. That’s the adjective Dr John Maher, an immunologist, uses when describing the impact of CAR T-cell therapies on blood cancer.
Thanks to these treatments, in which immune cells are genetically engineered to seek out and destroy cancer, patients who had seemingly run out of options are going into remission, or have even been cured, by a single dose.
Seven CAR T therapies have been approved to treat leukaemia and other blood cancers in the US and Europe since 2017, and four of these are available on the NHS.
However, solid cancers – tumours that arise in the breast, bowel, lungs and other organs that account for 90% of cancer cases – are ‘a completely different kettle of fish’ and have remained largely impervious to the therapy, says Maher. Now, however, there is promise that CAR methods could be used to treat these challenging cases.
Dr. John Maher, Chief Scientific Officer at Leucid Bio
Maher is a pioneer in the field. He was the first to engineer and test second-generation CAR T technology in human T cells, and in 2004 established CAR T-cell research at King’s College, where he leads the ‘CAR Mechanics’ group, using CAR engineered T cells for immunotherapy. He now serves as Chief Scientific Officer at Leucid Bio, a biotech developing next-generation CAR T therapies.
‘I’ve been working on CAR T for over 25 years and for most of that time I’ve worked on solid tumours,’ he says. And the reason is not because I think life is too easy – it’s because that’s where all the cancer is. That, for me, is the real unmet need of this technology.’
Broadly speaking, there are three hurdles to overcome when treating solid tumours: finding a suitable target on the tumour’s cells, getting the treatment to the tumour and ensuring it works once it gets there.
The next generation of CAR T-cell therapies aim to address all of these.
Choosing a target
To make a CAR T-cell therapy, a patient’s blood is drawn and their T cells isolated and genetically engineered to express chimeric antigen receptors (CARs), proteins that recognise and target molecules on the surface of cancer cells.
Multiplied up in the lab and reinfused into the patient, the T cells then home in on and kill cancer cells bearing the target molecule.
However, healthy cells can express these targets too.
For example, CD19, a molecule targeted by CAR T therapies used in blood cancer, is expressed by most B cells. The destruction of healthy antibody-producing B cells by the CAR T therapy can leave patients open to infections, but they can be given immunoglobulin replacement treatment to boost their immunity.
Healthy cells in the body’s organs can’t be replaced so easily, of course, making it crucial to find a target that’s as specific to cancer as possible, says Maher.
A solution being pursued by Leucid, among others, is to target NKG2D ligands, a family of eight proteins that are expressed by cells when they are under stress, including DNA damage – a hallmark of cancer. More than 80% of cancer cells have these ligands.
Another challenge is that solid tumours tend to be heterogenous – that is, they’re made up of many different types of cell, not all of which will express the target molecule.
‘Even if your therapy gets into the tumour and picks out all of those malignant cells that express the target, those malignant cells that don’t express the target can grow through and your therapy will fail,’ says Maher.
However, different malignant cells in the tumour will likely express different members of the NKG2D family and, as Leucid’s CAR recognises all eight ligands, most, if not all, of the cancer may be covered, says Maher.
Other approaches include creating bi- and tri-specific CARs, which attack more than one target, and the incorporation of so-called suicide genes in the CAR T-cells.
If CAR T-cell therapy is attacking too many healthy cells and causing severe side-effects, the patient can be given a drug to activate the suicide gene. This triggers a chain of events that culminates in the death of the cells in the therapy.
Drug delivery
After you’ve identified a target, you need to get your drug to the tumour. When the therapies are infused into the bloodstream, they have direct access to blood cancers. Solid tumours, however, have to be found within the body’s organs and the cells have to live long enough to reach them.
Leucid’s solution is to hijack a system that tumours use to protect themselves: the CXCR2 receptor. This receptor attracts immunosuppressive white blood cells to tumours, helping them to fend off attack by the body’s immune system. Leucid has ‘armoured’ CAR T-cells with this receptor to direct them to the tumour.
What about simply injecting the CAR T-cell therapy into the tumour? ‘We had a clinical trial where we did exactly that,’ says Maher. ‘The problem is that intra-tumoral delivery doesn’t deal with metastases because, based on our experience, the cells largely remain at the site of injection.
‘And, of course, many of these metastases will be microscopic, so you can’t see from scans where to inject.’
Hostile tumour micro-environment
The challenges don’t end on reaching the tumour, where there are multiple obstacles to overcome if the CAR T-cells are to survive and thrive.
These include high interstitial pressure, which impedes the entry of any treatment, and lack of oxygen. Tumours also produce a host of cytokines and other small molecules that inhibit the CAR T-cells and, as he mentioned earlier, immunosuppressive white blood cells are also present.
Targeting cells that bear NKG2D helps here, too. Many of the immunosuppressive white blood cells found in tumours express the ligands, as do non-malignant cells such as fibroblasts. The ligands are also found in the cells that line the blood vessels that feed the tumour, says Maher.
Another strategy is to re-educate the immunosuppressive cells so that they turn on the cancer. Leucid plans to use the cytokine IL-18 to do this.
The idea is that the CAR T-cells would make their own IL-18. To avoid triggering a life-threatening cytokine storm, the cytokine would only be activated when the CAR T-cells are activated and in ‘killing mode’.
Solutions being developed by other teams include using CRISPR to rewire the metabolic pathways in the CAR T-cells to help them better endure the hostile tumour micro-environment. There’s also some recent research that suggests that altering the gut microbiome can lead to CAR T-cells working better and living longer.
Building out not down
Leucid's USP is the way it constructs its CARs. A CAR contains an antigen-binding domain, which recognises the target on the tumour cells; and a signalling domain, which instructs the T cells to attack. Traditionally, these are arranged linearly, one below the other.
Most companies still do this, but Leucid places them side by side.
This lateral configuration is closer to that seen in nature and enables the cells to survive longer in the blood and in the tumour. It also enhances the treatment’s potency, says Maher.
He adds: ‘I’ve never seen a satisfactory explanation as to why nature goes to the trouble of coming up with this arrangement, but when nature does something it has to be for a reason – and I pay attention.’
In pre-clinical studies, 50% of mice with solid tumours, including triple-negative breast cancer (a particularly hard-to-treat form of the disease), treated with a lateral CAR that targeted NKG2D ligands survived long-term. This compares with just a few per cent of the animals given a similar linear CAR.
Engineering the cells to express the CXCR2 homing molecule increased survival to 85%. Other experiments indicated that the lateral CAR T-cells lived on in the body for longer, which should help prevent cancer recurring.
A lateral CAR T-cell therapy with CXCR2 that targets NKG2D ligands forms the basis of LEU011, Leucid’s lead asset. A phase 1 clinical trial on patients with a range of refractory solid tumours is under way, with the first patient treated in April 2024.
As good as it gets
With so much going on, what does Maher think are the most promising advances in the field? He points to CAR T-cells that target claudin 18.2. This protein lies hidden between epithelial cells in the gastrointestinal tract. ‘But when a cell becomes malignant, it loses polarity and the claudin becomes accessible,’ he explains.
‘People have made CAR T therapies against claudin 18.2 and have achieved partial responses – which tend to translate into prolonged survival – in 57% of patients with stomach cancer.’ (In a partial response, a tumour has shrunk by around a third or more and, in complete response, it can no longer be seen in scans.)
The ‘best and shiniest data’, however, come from paediatrics, where researchers in Italy used a CAR T-cell therapy to treat relapsed or refractory neuroblastoma, the most common solid tumour in children.
Eight of the 27 children and young adults achieved a partial response and another nine had a complete response. This overall response rate of 63% is on a par with that seen in some blood cancers.
‘That’s as good as it gets right now in the solid tumour space,’ says Maher.
Laura Carney, Senior Associate and Patent Attorney at Mewburn Ellis, comments:
"It’s so exciting to see the progress John and his team at Leucid Bio have made over the past few years. While CAR T-cell therapies are now well-established options for the treatment of blood cancers, there remains a huge need for effective CAR T-cell therapies for the treatment of solid tumours. John and his team are making great strides in addressing this with their lateral CAR technology. With such fantastic pre-clinical data, and with phase 1 clinical studies ongoing, we are looking forward to following Leucid’s next chapter."
Written by Fiona MacRae.
