Pembrolizumab, an immunotherapy treatment initially approved for advanced melanoma, recently became the first drug to be approved through the UK’s early access to medicine scheme, which gives patients with life threatening or serious conditions access to medicines that are unlicensed or off-label.
The scheme is great news for patients. But also from a scientific point of view. Immunotherapy, which uses the body’s own defence mechanism, is at long last becoming accepted as a frontline treatment for cancer, taking its place alongside conventional chemotherapy and radiation-based treatments.
The readiness of melanoma skin cancers to become malignant and spread to other parts of the body makes them deadly if not caught early. Pembrolizumab is an antibody that acts on the immune system to allow it to recognise cancer cells, triggering an immune response rather than destroying cancer cells directly.
The antibody had to be humanised, so it wouldn’t be recognised and hence destroyed by the immune system itself. The viable antibody that formed the basis of pembrolizumab was developed by MRC Technology at our laboratory in north London.
Pioneered by Edward Jenner
While Pembrolizumab and much of the basic research that underpinned it was carried on in the UK, the idea of immunotherapy dates back to Edward Jenner in the late 18th century.
Jenner’s pioneering work on smallpox is said to have saved more than 530m lives, but it is only in the past 40 years that the theory of targeting antibodies to treat cancer began to be taken seriously as the shortcomings of other approaches became apparent. Surgeons noticed that, despite their successes in removing tumours, only a few cells needed to escape for patients to relapse. Cytotoxics (the toxic drugs used in chemotherapy) and radiation-based treatments also tend to have blanket effects – killing both cancerous and healthy cells with often intolerable side effects.
The key was to find ways to allow the immune system to recognise tumour cells which seemed somehow to be avoiding attack. A natural starting point seemed to be the various checkpoints that regulate the deployment of antibodies to attack threats to the immune system.
The first real breakthrough came with the development of ipilimumab in the US, a man-made or humanised version of an antibody that targets CTLA-4, a protein in the body that normally helps keep immune system T-cells in check. By blocking the action of CTLA-4, ipilimumab boosts the immune response against melanoma cells in the body. It was a major first step, awakening interest and investment in the field.
Next generation antibodies
Pembrolizumab is the next step as one of a new generation of antibodies targeting the PD-1 (programmed cell death protein 1) pathway. PD-1 normally acts as a brake on the immune system, preventing “overheating” and the release of T-cells. If it can be switched off, the immune system is free to attack tumour cells. Melanoma was again chosen as a good target because, although it can be treated with surgical intervention at an early stage, once metastasised it becomes inoperable.
In the initial study, which led to approval in the US last year, 72% of patients responded to the drug, meaning that their tumours shrank to some degree. Overall, 34% of patients showed an objective response, meaning that their tumours shrank by more than 30%, and their tumours did not re-grow.
Pembrolizumab has offered real hope for melanoma suffers. However, cancer researchers are now speculating that immunotherapies like this could be effective in treating other cancers, since they regulate general defence response and are so potentially not limited to one cancer form. Multiple trials have already been initiated, with new data soon due across a range of challenging cancer types, especially in non-small cell lung cancer and mesothelioma. We can expect other immunotherapies to appear in the near future. Coupled with more effective diagnostic tools, we really could be on the cusp of an extremely exciting new era in cancer treatment.