There has been much interest lately in a new class of treatment called PD-1 inhibitors – molecules that can reinvigorate a patients immune system to attack cancer cells.

Programmed death-1 (PD-1) receptors act as a point of interaction for T-cell lymphocytes, allowing the immune system to eliminate the cell from the body and prevent any abnormal tissue growth. In cancer cells, programmed death ligand (PDL-1) is used as a means to negatively regulate the immune system by interacting with PD-1 receptors. Unlike other cell-cell interactions, PDL-1 activation of PD-1 receptors prevents T-cell elimination of cancer cells, essentially cloaking them from the immune system. The aim of PD-1 inhibitors is to prevent this interaction occurring, unveiling cancer cells to the immune system.

Presenting the New Wave of Cancer Treatment

Much of the hype surrounding PD-1 inhibitors was due to their unveiling last year at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) where they were discussed in the context of treating the most dangerous form of skin cancer – melanoma. In an original study into their efficacy, PD-1 inhibitors were shown to be significantly successful in a range of cancers, most notably non-small cell lung cancer (NSCLC), renal cell cancer and melanoma. The response rates in each cancer respectively (whether partial or complete) were 18%, 27% and 28%, meaning approximately 1 in 4 or 5 patients showed a clinical response to their treatment. Although this may seem a small percentage of patients, their responses were long-lasting, some patients showing a response to the drug after 1 or more years.

The interaction of interest above is between PD-1 and the ligand B7-H1. In panel A, the PD-1/B7-H1 interaction prevents the release of toxic substances that can kill the tumour cell. In panel B, an antibody structure has interfered with the PD-1/B7-H1 interaction, allowing the T-cell to release toxic substances leading to cancer cell death.

Present Day Promise

All of this however was found almost exactly one year ago and recent published results have emphasized just how effective these drugs can be. Major successes have been found in two forms of PD-1 inhibitors, the catchily-named Lambrolizumab and Nivolumab, both of which are fully human antibodies. A further success was found in a slightly different inhibitor of the PD-1 interaction pathway that targeted PDL-1 instead of PD-1 receptors.

Lambrolizumab caused advanced melanoma tumour shrinkage of more than half of its original size in 54 of 135 patients and in 6 of the 57 patients who received the highest dose of the drug, their tumours completely disappeared.

Likewise, Nivolumab also produced encouraging results in advanced melanoma, producing a tumour shrinkage of more than half in 21 out of 53 patients and a complete response in 3 out of the 17 patients receiving the highest dose. These responses were achieved when Nivolumab was used in conjunction with the administration of another treatment at the same time. The most remarkable factor of Nivolumab responses was their speed, sometimes after only a few weeks of treatment.

Finally, the PDL-1 inhibitor also produced a significant response in a range of cancers, including melanoma, lung and kidney cancers. Not much information has been disclosed regarding this alternative therapy although it is currently entering trials for all of the aforementioned forms of cancer. However, the fact that it is producing some sort of response in notoriously hard to treat lung cancers is very promising indeed.

Immunotherapy

One of my previous blog posts regarding immunotherapy showed how effective reinvigorating the immune system could be in treating multiple myeloma as well as other forms of cancer. Although PD-1 inhibitors are not necessarily directly altering a patients immune cells, they are aiding in re-activating a patients natural response to oncogenic growth.

The exciting news regarding this form of treatment is that they completely polarize traditional chemotherapy and radiotherapy treatments in their range of short and (potentially) long term side effects. In fact, in all three forms of the PD-1 inhibitors, the drug was well tolerated and only a very small percentage suffered any adverse effects (it should be noted that in three cases, patients died from pulmonary toxicity in the original 2012 study). It is too soon to tell if there are particularly potent long term effects as a result of PD-1 inhibitors but the fact that they have shown a response rate and low side effects in treatment periods lasting up to two years suggests that they are not particularly toxic in the long term.

A further observation to take note of is the sub-analysis performed on tumour tissue in relation to PDL-1 expression and treatment response rates. In 9 out of 25 patients who tested positive for PDL-1 expression, treatment was significantly effective whereas in patients who proved negative for PDL-1 expression, treatment response was non-existent. Results such as these suggest a diagnostic role for PDL-1 as a biomarker to treatment response using PD-1 inhibitors, an attribute that is not always available for other cancer treatments.

Gathering Momentum

In March of this year, it was reported that three people had been cured of what would usually be a fatal diagnosis of acute lymphoblastic leukaemia (ALL) – one patient was cured within 8 days. Their miraculous response was due to the engineering of their immune systems T-cells to target a molecule called CD19 which is only present in B-cells (the primary cells that have mutated in ALL). In much the same way as PD-1 inhibitors, this engineering of T-cells has resulted in a reboot of the patients own immune system in order to produce an incredible response to a deadly disease.

It is now becoming increasingly evident that personalisation of treatment and immunotherapy are becoming more and more established as a true cancer treatment when they were originally thought of as pipe dreams. This kind of treatment really is making a difference and it will be all the more exciting to see just how the field will progress. In regards to PD-1 inhibitors, Dr. Antoni Ribas – who presented the class of drugs at ASCO in 2012 – claimed them to be the “most impacting” recent development in melanoma treatment. It’s easy to see why.

References

The March 2013 New Scientist article regarding the curing of acute lymphoblastic leukaemia:

http://www.newscientist.com/article/mg21729104.100-gene-therapy-cures-leukaemia-in-eight-days.html

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