Dr Ludwig Dubois researches the use of immunotherapy to fight cancer

Wake up, immune system!!

He knows for sure that they are on the right track. They first saw it in mice, then in a small group of patients with advanced cancer, and now they are about to give a larger group of patients the new, experimental treatment. Because there must be something to it. Something that left 75% of the mice tumour-free for 150 days after the treatment. Something that prevents two of the six patients with advanced cancer from getting sicker for two years. Dr Ludwig Dubois and his colleagues are researching the use of a combination of radiation and immunotherapy to fight cancer. “Cancer can grow in humans or animals because the immune system no longer recognises cell mutations. We actually give the immune system a good wake-up call: go and do what you are meant to do.”

The treatment as a car

Immunotherapy comes in many forms. Ludwig Dubois and his colleagues use a specific molecule (I.e. an immunocytokine based on Interleukin-2). This molecule gives the immune system a big boost after it has been delivered directly to the tumour through the patient’s blood. In combination with a single dose of radiation, this therapy appears to be very effective. Especially if this is also done in combination with yet another molecule that counteracts the suppression of the immune system—the immune checkpoint inhibitors. Dubois: “We compare it to a car on a downhill slope. Irradiation is the GPS, the immunotherapy is pushing the gas pedal and the immune checkpoint inhibitors take the foot off the brake pedal.”

Surprisingly good results

To their own surprise, the initial results in mice (even without the inhibitors) were spectacular. “Mice with a tumour recovered completely in 75% of the cases and they were still cancer free another 150 days thereafter. When they were subsequently injected with tumour cells again, the immune system in most cases recognised the cancer and cleared it out spontaneously. So, you actually train the organism to clear out the same cancer in the future as well.” And what about metastases, which are sometimes not even detected? “Twenty per cent of the metastases were also eradicated long term in our mouse model, without them being irradiated.”

What is that, a mouse model?

A mouse model, in layman’s terms, is a mouse that has been specifically bred for animal testing, with certain genetic traits and a susceptibility to a certain type of disease (in this case a tumour). Sensitivity to this specific immunotherapy is also developed in these mice. “The Interleukin-2 variant that we use only works in mice and in humans.” The reason that Dubois cannot do research without animal testing is the fact that an immune system cannot yet be fully replicated in the lab.

Maastricht is also looking for alternatives

They are working very hard on this, also in Maastricht. “Of all the mice used for research, we freeze the spleen and lymph nodes, which is actually the immune system. We try to cultivate these cells in vitro, in a petri dish. After this, we can add cancer cells, possibly along with another drug and then measure the response. In the future, we think that we will also be able to screen for whether a patient would respond well to a certain therapy or would be resistant, which appears to be the case for many types of chemotherapy.”

Necessity and ethics are paramount

Replacement is therefore still in the distant future for this type of research, but reduction and refinement have long been a daily practice. “In the 17 years that I’ve been doing this work, I’ve always considered every test very strictly: are lab animals really needed and what is the minimum number that we need? Every experiment is ethically reviewed and I wouldn't want it to be any different. It must be necessary. You really have to come up with good arguments and a solid foundation, as well as why an alternative is not yet viable for you. That process has become much more laborious in the past 17 years and I’m happy to accept the bureaucracy that’s involved. If that substantiation is there and patients can possibly be helped with it in the future, I find it acceptable—even when it comes to larger animals, such as goats or dogs. The day that the scientific community can create an immune system without lab animals, I’ll sign up immediately. But we’re not there yet.”

The next follow-up study

First, the METC medical ethics review committee (Medisch Ethische Toetsings Commissie) must approve the study of 100 patients with non-small cell lung cancer and a maximum of five metastases, after which it can be conducted in various European institutions. Their primary tumour will be irradiated in combination with the two therapies that press the gas pedal of the immune system and release the brake. And all there is left to do is just hope that the car will cruise to its destination like a charm.

Dr Ludwig Dubois works together with Prof. Philippe Lambin and their team is affiliated with the UM research school GROW, where the cancer research is based. For the study in 100 patients spread across various European research institutes (the phase 2 study), they received a 6.5 million euro grant from the European Commission.