The establishment of Chimeric Antigen Receptor (CAR) T cell immunotherapy as a treatment for refractory and relapsed B cell leukaemia demonstrates that genetic modification of immune cells to circumvent tumour cell immune escape is a powerful strategy to combat paediatric cancers. However, efforts to develop effective CAR T cell therapies for solid tumours face a number of challenges: establishing an effective dose, route of administration, tumour cell mediated dampening of immune cell function, and overcoming heterogeneous antigen expression across the tumour cell population.
We have developed reagents and methodology to generate CAR T cells specific for Erythropoietin-producing Hepatocellular receptor tyrosine kinase class A2 (EphA2), expressed on a range of paediatric solid tumours. We showed that EphA2 redirected CAR T cells specifically targeted and killed various EphA2+ pediatric cancer cell lines in vitro, alongside secretion of cytokines. In an in vivo osteosarcoma mouse model, injection of EphA2 CAR T cells directly into established tumours resulted in complete regression of tumours, and extended survival of mice compare to mice receiving control CAR T cells or vehicle alone. We also tested the efficacy on systematic delivery of CAR T cells. Further work focussing on effective clinical CAR T production, safety and possible off-target effects, improve design of gene therapy vectors and delivery, and combinatorial testing of EphA2 CAR T cells with CAR T cells targeting alternative antigens, or immune checkpoint blockade will elucidate a way forwards effective clinical usage of CAR T cell therapy for refractory and/or recurrent pediatric solid tumours.