New hopes of care from CAR-T for brain cancers in children: a mix of gene therapy and drug therapy with a powerful anti-cancer action inhibits the growth of diffuse midline gliomas. These are very aggressive brain cancers, inoperable and – until today – with no effective treatment available. The new therapy was developed by the researchers of the Bambino Gesù Children’s Hospital in collaboration with the National Health Institute, Policlinico Gemelli and Institute of Cancer Research in London. The results of laboratory tests pave the way to the future human experimentation. The study was published in the scientific journal Neuro-Oncology.

The “diffuse midline gliomas” are tumors typical of pediatric age, in most of cases due to the mutation of protein H3K27M. They develop in the midline structures of the brain, particularly in the portion of the encephalic trunk regulating vital functions such as breathing and the cardiac activity. These cancers are very aggressive, tend to spread rapidly and to reach in depth penetration. Due to their position, they cannot be surgically removed. 

In Italy, about 20-25 cases of gliomas located in the brain pons are diagnosed in pediatric age, with a peak incidence between 5 and 10 years of age. Average survival is very low (9-12 months) and less than 5% of children survive 5 years after diagnosis, despite radio and chemotherapy treatments. Due to the heterogeneity of gliomas and the difficulties for drugs to overcome the barrier that protects brain tissues to reach the tumor, it has not been possible to identify an effective cure to date.

The study coordinated by the Oncohematology Research Area of Bambino Gesù Children’s Hospital, directed by Prof. Franco Locatelli, was conducted in the laboratory starting from the tumor cells of patients affected by glioma undergoing biopsy. The investigations on tissues, on cells derived from neoplasia, and on animal models, have allowed to identify an antitumor therapy never tested before, based on the use of an experimental drug (Linsitinib) in combination with genetically modified T-lymphocytes (CAR-T cells).

The drug, identified through a specific screening, is a specific inhibitor of IGF1R protein (molecule present on the membrane of cancer cells) capable of exerting a direct antitumor action on the diffuse midline glioma cells. CAR-Ts, on the other hand, have been programmed to recognize – and kill – cancer cells by aggressing a protein on their surface: the GD2 antigen (GD2-CAR-T).

The new combination therapy, tested in laboratory on several models of midline glioma, has shown it is able to inhibit the growth of tumor. Researchers also showed that the combination produces a more effective anticancer effect than the two treatments used separately: the drug amplifies the activity of CAR-T cells, and it is possible that CAR-T cells can “make way” for the drug in overcoming the protective emato-encephalic barrier.

The research carried out by Bambino Gesù was supported by Children with Cancer UK, AIRC, the Ministry of Health, AIFA, the Mia Neri Foundation, the Heal Foundation, DIPG Collaborative, and the Veronesi Foundation.

The diffuse midline gliomas are still lacking a treatment, but «the preliminary results of the study are encouraging» explains Prof. Franco Locatelli Director of Experimental and Precision Medicine at Bambino Gesù. « The new treatment strategy has provided promising pre-clinical results and might represent the first step to successfully treat a proportion of patients affected by this terrible form of cancer».  

As underlined by the researchers, before moving to human experimentation, the best ways to deliver drugs and CAR-T to the tumor site will have to be finetuned, and the therapeutic mix will need to be tested on more complex tumor models, allowing us to anticipate and evaluate the immune and inflammatory response in patients.

The scientific relevance of the Bambino Gesù study, in particular for the treatment prospects linked to the development of the new combined therapy, was also highlighted in a recent leading article published in the Neuro Oncology journal.