Scientists discover why immunotherapy drugs don’t work for some cancer patients

By Mark Waghorn via SWNS

Scientists have discovered why immunotherapy drugs don't work for some cancer patients - thanks to a failed clinical trial.

British patients were given an experimental pill for head and neck tumors. But immune-related adverse events meant the treatment had to be suspended.

What is more, mice given the the therapy also developed colitis, a bowel disorder.

When researchers went back through the data and analyzed patient samples they discovered what went wrong.

Their findings in Nature could lead to more effective medications.

Co-lead author Professor Pandurangan Vijayanand, of the La Jolla Institute, California, said: "This work shows the importance of learning from early stage clinical trials."

The international team found intermittent dosing could be a valid strategy that combines sustained anti-tumor immunity with reduced toxicity. A patient trial is now being planned.

Co-lead author Prof Christian Ottensmeier, of Liverpool University, said: "In the oncology world, immunotherapy has revolutionized the way we think about treatment.

"We can give immunotherapies to patients even with metastatic and spreading disease, and then just three years later wave goodbye and tell them their cancer is cured. This is an astounding change."

Unfortunately, only around 20 to 30 percent of solid cancer patients given immunotherapies go into long-term remission.

Some people see no change after immunotherapy, but others develop serious problems in their lungs, bowel, and even skin during treatment.

These side effects can be debilitating, even fatal, and these patients are forced to stop receiving the immunotherapy.

In the failed trial, patients were given an immunotherapy drug called a PI3Kδ inhibitor - proven effective for lymphomas but not yet tested in solid tumors.

They work by blocking immune cells called Tregs. Oncologists inhibit them inside tumours to fuel cancer-killing cells.

Prof Vijayanand said: "Having an oral tablet that can take off the brakes - the Tregs - can be a great asset for oncologists."

Unfortunately, 12 of the 21 patients had to discontinue treatment early because they developed colitis

He said :"We thought this drug wouldn't be toxic, so why was this happening?"

Genomic sequencing showed that in the process of increasing tumour-fighting T cells, the drug also blocked a specific Treg cell subset from protecting the colon.

Without Tregs on the job, pathogenic T cells, called Th17 and Tc17 cells, moved in and caused inflammation and colitis.

It was clear that the cancer trial patients had been given a larger dose than they needed.

The immunotherapy had thrown the delicate composition of immune cells in the gut out of balance.

The pathway that leads to the toxicity seen in the new study may be broadly applicable to other organs harbouring similar Treg cells.

Co-author Prof Mitchell Kronenberg, also from La Jolla, said: "This research illustrates how you can go from a clinical study to a mouse study to see what's behind toxicity in these patients."

Lymphoma patients in previous studies had been given several prior therapies leading to an overall immunocompromised state.

This means the lymphoma patients didn't have the same type - or the same magnitude - of immune response upon PI3Kδ inhibition.

Meanwhile, the head and neck cancer patients were treatment-naive. Their immune system wasn’t compromised, so the immune-related adverse events were both more rapid and more pronounced.

Overall, the new study shows the importance of studying personalised therapy doses and schedules.

Ten years ago there was only had one type of immunotherapy to offer. It either helped a patient or it didn't.

Doctors today have a rapidly growing library of immunotherapies to choose from.

The study in Nature is the first to determine which therapeutic combinations are most effective in individual patients - and the best timeline for giving these therapies.

Last year the researchers showed the potential importance of giving immunotherapies in a specific sequence.

Prof Vijayanand said: "If you design your clinical trials well and apply sophisticated genomics, you have a lot to learn. You can figure out what's happening and go back to the patients."

Prof Ottensmeier added: "This study has been an extraordinary collaborative effort. It has taken groups of medical oncologists, surgeons, research nurses, our patients, and scientists - all working together on two sides of the pond."