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Paolo Rossi Castelli23 September3 min read

Immunotherapy: testing to see if it works in advance

Some patients gain no benefit from the most innovative cancer therapies, for reasons as yet unknown. US researchers have identified a marker to avoid unnecessary treatments.

After almost ten years of research, oncologists at the Memorial Sloan Kettering Cancer Center in New York have achieved a breakthrough by identifying a marker of sensitivity to cancer immunotherapy.

This is a substance, set of substances or variants in the genetic code that make it possible to understand whether or not a specific patient will respond to the most advanced cancer therapies (for example, so-called checkpoint inhibitor therapies, which are based on ‘waking up’ and strengthening the patient's own immune system to beat tumours) before starting treatment.

It has been known for some time that, for reasons as yet undetermined, a certain percentage of patients do not respond, or respond unsatisfactorily, to these treatments. This means that these people will waste precious months, suffer side effects from medicines and spend money needlessly (immunotherapy drugs, which are almost all monoclonal antibodies, are very expensive).

Over the years, researchers have tried to identify patients for whom cancer immunotherapy will have a good level of success beforehand, through a number of markers, but none of these signs has ever appeared entirely clear or reliable.

The New York researchers therefore decided to analyse a large number of possible new markers to see whether or not there were any other promising candidates.

They checked the blood of 94 people with bladder tumours and 188 patients with metastatic melanomas (two kinds of cancer treated with immunotherapy). They measured a hundred possible markers in blood samples from the days immediately before the therapy started and hit the jackpot.The LAG3 Marker

As reported in Science Translational Medicine, the researchers focused on a possible marker called LAG3 (lymphocyte-activation gene 3), a protein found in T lymphocytes, the immune system’s vital cells.

The researchers found that patients with high levels of LAG3 (who they called the LAG3+ patients) responded much worse, or even not at all, to immunotherapy treatment, compared with those (LAG3- patients) who had a lower amount of this protein on the outer wall of the T lymphocytes.

As a result, LAG+ patients had a much shorter survival time than LAG- patients.

In particular, the average reduction in lifespan was more than four years for melanoma patients (22.2 months survival after immunotherapy for LAG+, compared to 75.8 months for LAG-). Bladder cancer patients also showed similar results in terms of treatment response, overall survival and progression-free survival (i.e. the length of time in which the tumour shows no signs of progressing).

Why does this happen?

The LAG3 protein inhibits the immune system to avoid problems like autoimmune diseases in healthy patients. In people with cancer, however, this can create a boomerang effect.

Further studies will be needed to see if LAG3 can become an effective and safe parameter on a large scale, but it is very promising.

The technique is also easy to apply. "You take a simple blood sample and in a couple of days you have the information you need to make a decision on which therapy to use... I'd say it doesn't get any better than that," confirms Margaret Callahan, a researcher at the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering, who coordinated the study. “Of course, there is still a great deal of work to be done before the results of our research can be clinically applied to patients, but we really believe we can do it.”

The hope is also that new drugs (not just 'predictive' tests), based on the role of the LAG3 protein, will also be developed to fight certain forms of cancer more effectively.


Paolo Rossi Castelli

Journalist since 1983, Paolo has been dealing with scientific divulgation for years, especially in the fields of medicine and biology. He is the creator of Sportello Cancro, the site created by on oncology in collaboration with the Umberto Veronesi Foundation. He collaborated with the pages of the Science of Corriere della Sera for several years. He is the founder and director of PRC-Comunicare la scienza.

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