A new step in anti-cancer treatments

DR. Margherita NORELLI
            INSIDE 513Cell therapies that use CAR-T technology represent a real revolution in the fight against blood cancers: this technology consists of genetically engineering immune system cells (specifically: lymphocytes) to make them capable of recognising and eliminating tumours. However, the extraordinary effectiveness of CAR-T lymphocytes is accompanied by the risk of severe toxicities, including the common cytokine release syndrome (CRS) – cytokines being molecules with high inflammatory potential – and the rarer but unfortunately sometimes fatal neurotoxicity.
Now, however, a discovery by a team of researchers from San Raffaele Research Hospital, made possible through the support of the Italian Cancer Research Association (AIRC) and published in Nature Medicine, promises to make treatment with CAR-T lymphocytes much safer. Scientists led by Dr. Attilio Bondanza, former researcher at Università Vita-Salute San Raffaele and now at Novartis in Basel, have discovered the molecular mechanism that is the origin of the toxicities, and have demonstrated the potential efficacy of a drug already in use for arthritis in preventing and treating them.



          CAR-T lymphocytes express so-called “chimeric” receptors on their surfaces, designed in the laboratory, and constructed by assembling different molecules. These chimeric receptors enable the lymphocytes to recognise tumour cells selectively. The basic idea behind this therapy is to instruct the immune system to distinguish diseased cells from healthy ones, Dr. Attilio Bondanza explains. Not an easy task, as the immune system is trained by evolution to be very cautious about attacking our own tissues. However, this is exactly what needs to be done in the case of a tumour.” Through genetic engineering, CAR-T lymphocytes become able to provoke an immune response against a tumour with unprecedented effectiveness. That is why the American FDA approved its use in 2017 for some blood cancers (lymphoblastic leukaemia in children, and lymphoma in adults). In Europe, approval by the EMA is expected by the end of 2018.
             As with any drug, their efficacy may be accompanied by certain side effects. CRS is quite a common syndrome in patients undergoing CAR-T lymphocytes therapy. It generally manifests within a few days of infusion, and can usually be controlled through the use of tocilizumab, a drug that inhibits the cytokine IL-6.
             After a few weeks, however, in a small but significant number of patients, a new disorder emerges, which to date has been very difficult to treat, and which can prove to be fatal: neurotoxicity.



            The first goal of the research group of Immunology, Transplant and Infectious Diseases Division at San Raffaele was to develop a humanised mouse model ‒ a mouse with an immune system that is very similar to that of a human ‒ able to reproduce for the first time both the therapeutic and toxic effects of CAR-T lymphocytes observed in humans, in order to study the nature of the CRS and neurotoxicity, and in particular to understand the relationship between the two. Through studying of this model, the group led by Dr. Bondanza has shown that neurotoxicity linked to CAR-T lymphocytes is caused by a different molecule, not IL-6, but IL-1, and has demonstrated the efficacy within the experimental model of anakinra, a drug that inhibits IL-1, and that was already on the market to prevent and treat arthritis. In addition, through studying the relationship between the two cytokines the researchers have shown that IL-1 is the first cytokine to be released, and is what triggers the chain reaction that also leads to the release of IL-6 and thus the onset of CRS.
            “This means that the administration of anakinra could combat both neurotoxicity and CRS adds Margherita Norelli, primary author of the work. The study is important because it not only suggests a pharmacological option that is already available for patients undergoing CAR-T lymphocyte therapy, but in particular because it demonstrates that the anti-cancer efficacy of these innovative therapies remains intact even when their inflammatory effects are blocked, concludes Dr. Attilio Bondanza. The next step will be to test anakinra, or other drugs that inhibit IL-1, on humans, with the ultimate aim of achieving a real benefit for an ever-greater number of patients.
Date: 05/07/2019
By: Nicola Quadri
Translation: TDR Translation Company
Editing: Victor Cojocaru