Tisotumab vedotin (TV), an innovative new drug, has shown promise in treating six different types of cancers.
A team at the The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, led a Phase I/II clinical trial comprising of nearly 150 people from the UK, US, Belgium, Denmark, and Sweden. TV was administered to patients with advanced solid tumours or in patients with drug-resistant forms of cancer with poor prognosis, including those with bladder, cervical, endometrial, oesophageal, lung, and ovarian cancer. It was reported that the drug had shrunk or stopped tumour growth altogether.
According to Professor Johann de Bono, Regius Professor of Cancer Research, “what is so exciting about this treatment is that its mechanism of action is completely novel — it acts like a Trojan horse to sneak into cancer cells and kill them from the inside”.
TV comprises a toxic drug that is attached to a human antibody, a type of protein that our immune systems produce to bind to pathogens and either tag them for destruction or inactivate them directly. The antibody binds to a receptor found abundantly on the surface of many types of tumour cells, called the Tissue Factor. This receptor is associated with tumour growth, metastasis, and angiogenesis, the formation of blood vessels tumours need to deliver them with nutrients. Its major role in tumour growth made the tissue factor a logical drug target.
By binding to the receptor with the antibody part of the drug, TV is internalised into the tumour cell and is trafficked to the lysosome, a membrane-bound sac in the cell. Enzymes inside the lysosome break up the linker between the antibody and the toxic component. This releases the cytotoxic drug called monomethyl auristatin E (MMAE) into the cell. MMAE halts the tumour cell cycle by disrupting polymerisation of microtubules, the strands of protein that are essential for cell growth and division. Eventually the cell dies as it is not able to progress in the cell cycle. MMAE may then also diffuse into the microenvironment and kill neighbouring dividing cells.
It was reported that the drug had shrunk or stopped tumour growth altogether.
The kind of death MMAE induces, known as immunogenic cell death, can stimulate the natural immune system to detect and respond to tumour cells, which otherwise often go undetected because they look like “self” cells.
Researchers believe that TV has manageable side effects in these patients, all of whom had late stage cancer. Side effects include nose bleeds, fatigue, nausea, and conjunctivitis. These have been credited to the underlying inflammation or increase in local expression of tissue factor in the affected area.
Professor Paul Workman of The Institute of Cancer Research, London, said: “It is exciting to see the potential shown by TV across a range of hard-to-treat cancers. I look forward to seeing it progress in the clinic and hope it can benefit patients who currently have run out of treatment options.”
Data from the first phase assesses the safety, tolerability and pharmacokinetics of TV, all of which are being improved in ongoing trials. How the drug can target such a large variety of tumours is still unknown and research is ongoing to uncover the potential mechanism behind the success of this revolutionary “Trojan Horse” drug.
Image Credit: Nephron