The world’s biggest pharma companies are pouring hundreds of millions of dollars into developing new immuno-oncology drugs – but what exactly are they?
Immuno-oncology is an exciting – and relatively new – type of immunotherapy that is specifically designed to fight cancer.
Unlike traditional cancer treatments such as chemotherapy, which essentially poison the body in a bid to kill off the tumour, immunotherapies work by stimulating the body’s own natural responses.
For a host of reasons, cancerous cells can sometimes go undetected by our immune systems, but immuno-oncology drugs help to lift this ‘cloak of invisibility’ and encourage the body to attack the cells.
This has obvious advantages given there is no need for invasive surgery or courses of toxic chemotherapy or radiation.
The first immuno-oncology drug was approved back in 2010 - sipuleucel-T for prostate cancer - and since then dozens have come to market, proving effective in treating melanoma (skin) and lymphoma (blood), as well as lung, breast and several other types of cancer.
There is more than just one type of immunotherapy as well.
CAR-T therapies made headlines here in the UK towards the end of 2018 when UK regulators reached a deal over pricing with pharma giant Novartis for its cutting-edge Kymriah treatment.
Kymriah is what’s called a CART-T therapy, which stands for chimeric antigen receptor T-cell.
As the name suggests the technology involves T-cells, white blood cells that help the immune system fight disease and infection.
CAR-T therapies re-engineer the blood to recognise cancer cells that have been hiding in the body that haven’t been destroyed.
This area of immuno-oncology has become a popular field of research with UK companies at the forefront of some of the latest innovations.
Several UK firms in CAR-T space
Leading the pack is Autolus Therapeutics, a spin-out from University College London, which is now listed in the US with a market capitalisation in excess of US$1bn.
Backed in its formative stages by Arix Bioscience PLC (LON:ARIX) and Neil Woodford’s Patient Capital, it is running five CAR-T programmes covering six blood-borne cancers and solid tumour indications.
It recently started dosing the second cohort of patients in the phase I clinical trial of MCY-M11, a chimeric antigen receptor that targets solid tumours.
There are also monoclonal antibodies, which help the immune system to spot and kill cancer cells. If a company’s drug ends in -mab (tremelimumab, for example), it’s probably a monoclonal antibody.
One of the best things about our immune system is its ability to tell the difference between normal and harmful cells. It uses checkpoints to do just that, which either turn up or turn down a signal.
But cancer cells are clever things, and they can often interfere with the responses to avoid detection.
Monoclonal antibodies trigger the immune system by attaching themselves to proteins on cancer cells, making it easier for the body to find and attack the cancer cells.
The anti-Clever-1 antibody which targets and eliminates Clever-1 antibody-positive tumour associated macrophages (TAMs).
TAMs are a class of immune cells present in high numbers in solid tumours.
Checkpoint inhibitors are the big money-makers
Checkpoint inhibitors are a particular type of monoclonal antibodies that help to flag up cancer cells to the immune system.
Cancer Research has a particularly good analogy: cancer can sometimes push a stop button on the immune cells, so the immune system won’t attack them. Checkpoint inhibitors block cancers from pushing this stop button.
Merck’s Keytruda is probably the most well-known monoclonal antibody. It is what’s known as a PD-1 inhibitor, and sales of the drug doubled last year to over US$7bn.
Peak sales could be as high as US$16bn, according to some analysts, as it takes a stranglehold on the massive lung cancer market.
Bristol-Myers Squibb’s rival PD-1 inhibitor, called Opdivo, used to be the biggest, but it was overtaken by Keytruda last summer. Still, at just shy of US$7bn, it wasn’t too far behind.
An upgrade of existing cancer drug Doxorubicin will be the first drug it takes into clinical trials.
Doxorubicin has been a standard prescription for soft tissue cancers for decades, but heart toxicity issues limit its use.
Avacta’s Pro-Doxorubicin can eliminate many of these problems because it is inert until it gets inside a tumour.
Porcupine inhibitors work by dialling down the Porcupine protein, which is the control switch for the Wnt pathway – known to be heavily involved in cell growth and division.
One of the players in this space is Redx Pharma PLC (LON:REDX), whose lead candidate RXC004 can be used as a combination partner as well.
There is a growing bank of research that suggests Porcupine inhibitors may also be very effective in tandem with checkpoint inhibitors such as anti-PD-1s, which lower or break cancer’s defence against the body’s immune system.
Redx plans to assess the drug in combination with a checkpoint inhibitor further down the line, something Swiss giant Novartis is doing with its Porcupine inhibitors.
Another example of inhibitor is AstraZeneca’s blockbuster Lynparza.
PARP – or poly-ADP ribose polymerase – is a protein that helps damaged cells to recover.
Taking a PARP inhibitor stops it from repairing cancer cells, which then eventually die.
Lynparza is currently approved in 65 countries to treat women with certain types of ovarian cancer and was granted priority review in the US as a possible treatment for prostate cancer.
“Priority review” in the US means the application for a drug will be assessed within 6 months compared to 10 months under standard review.
It is given to candidates which would yield significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions.
Similarly, the Orphan Drug Designation (ODD) status is assigned to new drugs for critical diseases that affect less than 200,000 people.
ODD status gives tax breaks, reduced fees and a 7-year period of marketing exclusivity for the drug concerned.
Midatech Pharma PLC (LON:MTPH) received ODD status for MTX110, a treatment for Diffuse Intrinsic Pontine Glioma (DIPG), an aggressive and fatal form of childhood brain cancer with no approved treatment yet.
It is an acid which can be delivered directly in and around the tumour via a catheter system.
This technique allows for the administration of high drug concentrations while avoiding the spread of too many toxins in the body.
Cytokines are a bit more complex to explain. In simple terms, they are a group of proteins that play an important part in boosting the immune system.
They have a lot of control over the body’s response to an antigen – a toxin or foreign substance which causes the immune system to start making antibodies.
If there is an imbalance or their production is altered, this can lead to tumours developing.
Scientists have developed man-made versions of interferon and interleukin, which are types of cytokines found in the body.
On the flip side, if the body is producing too many cytokines, Janus Kinase (JAK) inhibitors can stop the proteins from being excessively activated. These have proved useful in treating cancers like renal cell carcinoma and melanoma.
Preclinical programmes have been mapped out for each discovery with the aim of getting them into the clinic in 2020.
Tumour-infiltrating lymphocytes (TIL) therapy
TIL are white blood cells surround or oppose tumour cells. In this kind of therapy, TILs are collected from the tumour during a biopsy or surgery to be then infused back to the patient.
In short, this treatment uses altered tumour cells to destroy the tumour itself.
It requires a brief course of chemotherapy to help TIL infusion attack the cancer.
Metastasis are tumour outbreaks developing away from the primary location.
There are also some cancer vaccines, although it is important to note that these don’t work like regular vaccines.
Rather than working to prevent an infectious disease, they are used to stimulate an immune response to attack existing cancer cells.
Once injected into the bloodstream, cancer vaccines should activate an immune response to help fight the cancer.
It is designed to prevent infection from certain types of human papillomavirus (HPV), which is responsible for around two-thirds of cervical cancer cases. Last year, it brought in sales of US$175mln for GSK.
For the treatment of choroidal melanoma, Arix Bioscience has developed a formulation to be used in conjunction with laser.
AU-011, which has been fast-tracked and granted ODD status, is injected in the eye and followed by laser treatment all in the physician’s office.
It is being studied to attack the tumour without affecting the patient’s vision.
A look at the small caps
While the likes of GSK, AstraZeneca PLC (LON:AZN) and Merck might have more high-profile - and expensive - programmes in the works, there are plenty of smaller companies out there looking to rise up the ranks.
TIziana Life Sciences PLC (LON:TILS) is one of those. One of the drugs it is taking through the clinic is Milciclib, a cyclin-dependent kinase (CDK) inhibitor.
It works to reduce levels of microRNAs in the body, which are thought to help supply blood to tumours. Interestingly, it also a potential tyrosine kinase (TYK) inhibitor.
The drug furthest down the clinical pathway is SCIB1, an antibody that stimulates the immune system to attack tumour cells expressing certain antigens.
A phase II trial of SCIB2 in skin cancer is due to get underway within a matter of weeks.