Immunotherapy prospects receive boost

2 December 2014

You wait three years for an advance, and then two (at least) arrive at once.  After three decades of virtual silence from the field of cancer immunology research, reports this week suggest a significant step forward is within view.

Last week the New England Journal of Medicine reported a study of 64 patients with melanoma who had been treated with the immunotherapy drug ipilimumab. Half the patients responded to treatment, actually a relatively high percentage, as the majority of patients of don’t. Attempting to understand why, researchers led by a team from Memorial Sloan Kettering Cancer Centre in New York examined the patients’ DNA and then the genetic profile of their tumours. 

They discovered that some patients had a series of genetic mutations that caused the cancer cells to develop peptide antigens, making them more visible to the patient’s own immune system. This research is in very early stages, but could eventually lead to the ability to identify which of the minority of patients with melanoma could genuinely benefit from the ipilimumab, which costs nearly £77,000 for a course of treatment.

Cancer Research UK's Dr Quezada observed: "This is the first time we've had an idea of what the immune system actually 'sees' on a tumour. Until now, it's been hot topic of debate ".

The same team, led by Dr Timothy Chan, also found evidence that the more mutated a tumour’s genome, the more likely it is that immunotherapy will work. However, it is by no means all about quantity – quality matters too. Excitement among the New York team at identifying what the immune surveillance ‘sees’  was matched by that of researchers looking at urothelial bladder cancer  who may have found a way to make ‘seeable’  certain  otherwise ‘invisible’ tumours. 

Urothelial bladder cancer (UBC) is associated with notably poor outcomes, particularly among those for whom chemotherapy is ineffective or highly toxic.  A feature of UBC is high levels of genetic mutations. Whilst this may help alert the body’s immune system, some tumour cells have adapted the body’s disease fighting capacity for their own purposes.  

PD-L1 (programmed death-ligand 1) is a protein thought to be expressed by the body to inhibit the immune system in response to  key events,  for example during pregnancy.  Some cancers, including UBC, have evolved cells that are able to evade detection by the body’s immune surveillance system, by upregulation of PD-L1,.

By attacking the cells with a modified variation of anti-PD-L1 antibody MPDL3280A, the Yale team were able to supress expression of the protein; the tumours shed their camouflage, exposing them to the surveillance and therefore making them susceptible to this existing immunotherapy drug.

They studied 68 patients with advanced bladder cancer, all of whom had received chemotherapy and a life expectancy of only months. Of those whose tumours were deploying PD-L1, more than half showed signs of recovery; two patients showed no signs of cancer after treatment. One in ten patients responded to the experimental therapy even if PD-L1 was not present in the tumour.

MPDL3280A received breakthrough designation status by the US Food and Drug Administration (FDA) earlier this year, and could be in wider use by the end of 2015. The drug may prove of particular value in treating older patients who are more vulnerable to the toxicity of chemotherapy. 

Separate studies from the American Society of Clinical Oncology and Yale University have also reported significant success with similar trials of immunotherapy treatments. Although modest, taken together these results could prove more than the sum of their parts as personalised healthcare includes tailoring to the pathogen as well as the person

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