CAR-T cell therapy strikes again!
Chimeric Antigen Receptor (CAR) T cells targeting epidermal growth factor receptor (HER2) showed excellent pre-clinical efficacy in vitro and induced durable regression of medulloblastoma in xenograft mouse models. Let’s go introduce the protagonists of this study.
Medulloblastoma is the most frequent cerebral tumor in children aged between 2 and 7. Standard therapies include radiotherapy and chemotherapy, which in fact prolong survival but at the same time produce long-term side effects. What about using immunotherapy instead?
HER2 is a gene encoding a surface protein called c-erbB-2 that belongs to the family of tyrosine kinase membrane receptors. Such receptors are composed of two parts or “domains”, one on the extracellular side of the membrane and the other on the cytoplasmic side: the first binds the ligand, the epidermal growth factor; the second is an enzymatic site, which phosphorylates (= attaches a phosphate chemical group) an amminoacid called tyrosine in the target proteins, modulating their activity or localization and possibly producing changes in the cells phenotype. In particular, HER2 modulates signalling pathways associated with cell proliferation and differentiation. In multiple adult and pediatric tumors, including breast or gastro-intestinal cancer, there is a mutation that makes an excess of HER2 protein: as a result, cancer cells proliferate without any control and become resistant to standard therapies. For this reason, HER2 has become a target of choice for immunotherapy.
CAR-T are “super” soldiers of the immune system bearing a genetically engineered chimeric receptor that combines the specificity of an antibody (antigen-binding domain) with the cytotoxicity of a T cell (signaling domain). Normal lymphocytes are isolated from the patient’s peripheric blood, “armed” with a DNA sequence encoding a chimeric receptor that recognizes molecules, or antigens, specifically exposed on the surface of tumor cells, and then re-injected back in the patient. CAR-T can be virtually directed against any tumor-associated antigen and as soon as they bind it, the fight begins: cytokines and perforating enzimes are released and literally destroy the cancer cell.
HER2 is overexpressed in many medulloblastomas and has been used as a CAR-T target before. In this study, second generation HER2-CAR-T cells enriched with additional co-stimulatory domains were effective against medulloblastoma without the same side effects as standard therapies. Pre-clinical results were promising and studies on non-human primates confirmed the lack of systemic toxicity upon administration.
We hope that CAR-T cell therapy will bring hope to people suffering from medulloblastoma as well as other tumor types.