Zirconium reveals cancer cells

A new cancer treatment that helps the immune system get rid of tumours is having spectacular results. Unfortunately it doesn’t work for everyone. Doctor in training Frederike Bensch found a way to predict who would benefit from the treatment.
By Christien Boomsma / Translation by Sarah van Steenderen

Frederike Bensch is late. She rushes through the cafeteria to get a quick sandwich, because she hasn’t eaten yet. She’ll only be at the Martini Ziekenhuis for another few months before she returns to the UMCG to become a lung specialist.

Her PhD is sure to be a success: after a long search, she has found a way to predict the success of a new cancer treatment. The results of her research were published in the top journal Nature Medicine on 28 November. She waited to schedule her PhD ceremony until the article was accepted, but now the date is set. ‘18 March’, she says happily.

She worked alongside a research team led by professor Liesbeth de Vries on the groundbreaking project. ‘Research like this isn’t done alone.’

Stealth mechanism

There ‘checkpoints’ – or proteins – attached to cancerous tumours that work as a sort of cloaking device, hiding cancer cells from the immune system. So the immune system fails to attack them. This year, the Nobel Prize for Medicine was awarded for discovering this stealth mechanism for cancer cells and figuring out how to turn it off.

‘When I started as physician-scientist around 2012, the first results of the study of treatment in patients with metastasised cancer came out. Inhibiting the proteins PD-1, PD-L1, and CTLA4 had incredible results,’ she said.

And patients didn’t only respond well to the immediate treatment; the results were often long-lasting, as opposed to regular chemotherapies.

Doozy

It was a spectacular discovery. But unfortunately, the treatment didn’t work for everyone. This was a bummer, because not only is the treatment very expensive, it also has a severe effect on the patients.

That’s because ‘you kind of take the brakes off the immune system’, Bensch explains. ‘That can lead to all kinds of immune responses, such as healthy tissue becoming inflamed.’  This includes inflammation of healthy bowels, healthy lungs, or healthy skin, which then has to be treated with anti-inflammatory medication. ‘In extreme cases, we have to stop the treatment’, says Bensch. ‘This treatment is a doozy.’

The medical profession is currently using immunohistochemistry to figure out which patients are eligible for treatment. A pathologist then dyes cells to check for the required number of checkpoints.

‘But that method isn’t a sufficient predictor’, says Bensch. ‘Patients with low expression rates can benefit from the treatment, while some people with high expression rates don’t respond at all.’

Better screening

This is because a data from a biopsy is only for a single moment in time, and only provides a picture of one spot on one single tumour. ‘But we’ve been seeing that the characteristics of a tumour don’t just change over time’, says Bensch. ‘It’s possible that we take a biopsy from the left side while the checkpoints are on the right. It’s also possible that one tumour does metastasise while another doesn’t. Or it might not metastasise today, but it will next week.’

That is where Bensch and her colleagues come in. Wouldn’t it be great if they find a better way to screen patients for this treatment? ‘At the UCMG we have a lot of experience with molecular imaging’, she says. ‘Ways to map out the entire body using PET scans, such as the HER2 for breast cancer.’

She used this knowledge as a model for her research into antibodies against the PDL-1 checkpoint. She was also backed by the American pharmaceutical company Genentech, which manufactures the inhibitor atezolizumab.

Zirconium

‘We labelled the antibody using zirconium, which is radioactive’, says Bensch. ‘Its radiation lasts much longer than fluorine, which we used before this. We then inserted it into the bloodstream using an IV.’

PET scans done after one hour, two, four, and seven days showed where the antibody had ended up. If the PDL-1 checkpoint was there, the antibody would stick to it, throughout the entire body.

‘We not only showed that the antibody reached the tumour, but it stayed there while it disappeared from the rest of the bloodstream’, says Bensch. Next, all the patients in the study, twenty-two in total, received the treatment. Patients who absorbed a lot of atezolizumab responded much better to it being used in the treatment.

‘We could show the result for each tumour lesion’, says Bensch. ‘Metastasis that had absorbed much of the labelled antibody according to the scan, had been beaten back more because of the treatment.’

Saving lives

Bensch’ study may have been small but it provided important proof of concept, she says. It was also important because it allowed her save lives. There were people involved in the study who weren’t eligible for the treatment originally.

She admits that it hasn’t been easy. She lost some patients. Three of them were in such poor health that they couldn’t even participate in the entire study. Others, however, responded beautifully. In three of them the cancer went into complete remission, while four people experienced partial remission. She saw eleven patients stabilise. ‘Statistically speaking, these people should be dead’, says Bensch. ‘But they’re still alive.’

Nederlands

05 December 2018 | 5-12-2018, 11:28