For the first time, a gene therapy with CAR T cells has been shown to be able to successfully treat neuroblastomas, solid tumors that can occur in childhood.
From the Bambino Gesù Pediatric Hospital in Rome comes news that could revolutionize the future of cancer treatment: a group of clinicians and researchers led by Professor Franco Locatelli has succeeded for the first time in using immunotherapy with CAR T cells to treat neuroblastomas , among the most aggressive tumors that can occur in children.
First time. Until now, CAR T cells, immune cells engineered to target specific tumors, had only proven very effective in treating blood cancers. As Locatelli, head of the research area and clinical area of Oncohematology, Cell Therapy, Gene Therapies and Hematopoietic Transplantation of the Child Jesus explains: «It is the first time that a study on the use of CAR T cells against solid tumors has achieved such encouraging results ».
The research that was published in the prestigious scientific journal New England Journal of Medicine, involved 27 children between the ages of 1 and 25 with high-risk forms of neuroblastoma, relapsing or resistant to conventional therapies (chemotherapy and radiotherapy). The response to treatment has exceeded 60% and the probability of survival without disease is significantly increased compared to the often poor prognosis of this type of tumour.
Neuroblastoma – what is it? Neuroblastoma is a tumor of the sympathetic nervous system that originates from neuroblasts, cells present in the sympathetic nervous system, and can arise in various parts of the body, among which the most frequent is the adrenal gland, the set of two small glands placed above each kidney.
It is the most common extra-cranial solid tumor (i.e. with a compact mass of tissue) in children, responsible for 11% of all childhood cancer deaths, and mainly affects children under the age of 5. Nearly half of patients have high-risk disease already at the time of diagnosis, and five-year survival after diagnosis is 40-50%.
Children who fail first-line treatments have very low chances of recovery and a long-term survival of between 5 and 10%. Hence the decision, says Locatelli, to “verify if therapy with CAR T cells was able to change the natural history of their disease”.
What therapy was used? CAR-T cells (the acronym stands for Chimeric Antigens Receptor Cells-T) are T lymphocytes (the white blood cells that normally recognize threats posed by viruses or malignant cells, retaining the memory of the attacks suffered) engineered to recognize and target a specific cellular antigen, such as those expressed by tumor cells.
The choice of target. To design the CAR T cells that were infused into patients, the researchers started from each patient’s immune cells, autologous T lymphocytes, which were then genetically modified to express CAR (Chimeric Antigen Receptor), a synthetic molecule, on their surface capable of specifically recognizing cancer cells. Neuroblastoma cells express high levels of a molecule called GD2 on the outer membrane, which has therefore been chosen as a target. By following this crosshair the modified T lymphocytes were able to locate and neutralize the diseased cells.
Those used in the study are third generation CAR T cells. Unlike the second generation ones approved for clinical use against blood cancers (leukaemia, lymphoma and myeloma) these included what is called a second costimulatory domain, a combination of molecules that increases the efficacy and persistence of the engineered T lymphocytes.
The engineered cells also contained a sort of “safety switch,” a suicide gene that blocks the action of T lymphocytes in the event of severe adverse effects of immunotherapy. Since a common and possible side effect of CAR-T-based therapies is cytokine release syndrome (fever, hypotension, hypoxia), this trick allows the rapid elimination of infused CAR-T within a few hours.
The results. The study carried out also thanks to the funding received from the AIRC, the Ministry of Health, AIFA and the Italian Foundation for the Fight against Neuroblastoma evaluated both the safety and tolerability of CAR T cells in various dosages (phase 1), and the efficacy in the treatment of tumors and the permanence of the cells in the organism (phase 2). The therapy has proven to be safe and effective. 63% of patients (17 children and teenagers) showed a response to therapy and 9 of these went into complete remission. The probability of survival up to 3 years (60% of cases) and of surviving without evidence of disease (36%) also increases. CAR T cells persist in the body up to 2-3 years after infusion, supporting the efficacy of the therapy.
A new therapeutic option. In addition to representing an additional weapon in the fight against neuroblastoma, even in children in whom these tumors have recently been diagnosed and in which elements of high risk for survival are present, research paves the way for the use of CAR T also for other solid tumours. A trial will soon begin in which the same type of CAR T cells directed against the GD2 target molecule will be used in pediatric and young adult patients suffering from various types of brain tumors.