A new clinical trial will inject genetically modified immune cells directly into the fluid surrounding the brain to treat children with high-risk brain tumours that have resisted surgery, chemotherapy, and radiotherapy. These aggressive childhood brain tumours have seen little improvement in survival for decades. The trial tests three innovations at once: a new DNA sequence that makes killer T-cells recognise tumour cells while sparing healthy tissue, a molecular switch that lets doctors turn the cells on and off with a drug, and direct delivery into the cerebrospinal fluid instead of the bloodstream. Crucially, patients will not receive chemotherapy beforehand—standard practice that increases toxicity and limits how many doses a child can safely receive. If the treatment proves safe and effective, it could offer a lifeline to children with no remaining options. Each patient can receive up to three scheduled infusions, with more allowed if they benefit. The trial plans to recruit 18 patients. Success would not only provide a new therapy for a devastating condition but also establish a delivery method that could be applied to other brain cancers and neurological diseases where the blood-brain barrier blocks treatment.
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Childhood brain tumours that cannot be surgically removed or are insensitive to chemotherapy or radiotherapy represent a major clinical unmet need in paediatric oncology. There has been little improvement in outcome for these patients in recent decades despite numerous clinical trials of new treatments. In this research proposal we are seeking to evaluate a new approach to this high-risk patient group through a phase I clinical trial in which a new treatment (chimeric antigen receptor: CAR-T cells) and new route of administration (direct injection of cells into the region of the tumour) is evaluated in patients lacking other treatment options. The principle underlying CAR-T cell technology is that a blood sample is taken from the patient, and the killer cells of the immune system (T cells) are genetically modified in the lab, so as to specifically recognise cancer cells, but not normal cells. These genetically-modified therapeutic cells constitute a "cellular therapy", and we term them "killer T-cells". Following safety and quality testing, the gene-modified killer T-cells can be administered back to the patient, and the effect on tumour growth can be evaluated by serial tumour imaging, and by collection and analysis of patient samples. In the proposed clinical trial, particular innovation lies in three main areas. Firstly, the particular genetic modification to be trialled is new; ie a new DNA sequence encoding a new molecular structure on the surface of the killer T-cells. This novel structure incorporates a new recognition component for the cancer cells, and also incorporates a molecular switch allowing the activity of the killer T-cells to be switched on and off by use of a drug. Hence the trial needs first and foremost to test the safety of this approach. Secondly, we will evaluate if these gene-modified killer cells work without giving prior chemotherapy treatments to the patients. Chemotherapy pre-treatment has been previously considered essential for function of injected killer T cells. However, the chemotherapy also can increase overall toxicity for the patient, and can limit the number of treatments that can be safely given to an individual patient. Thirdly, we will use a novel mode of delivery, which is direct injection of the gene modified killer T-cells into the fluid that bathes the brain (cerebrospinal fluid). This will act as an alternate efficient delivery system and potentially will overcome the limitations of delivering killer T cells to brain tumours by the traditional approach of injection into the bloodstream. Each patient will receive up to three scheduled infusions, with further infusions allowed if there is clinical benefit. It is planned that a total of 18 patients will be recruited.
Andre Lopes (Co-Investigator)Darren Hargrave (Co-Investigator)Friso Calkoen (Co-Investigator)Jasper Van Der Lugt (Co-Investigator)Jennifer Furman (Co-Investigator)Kristian Aquilina (Co-Investigator)Kshitij Mankad (Co-Investigator)William Anderson (Principal Investigator)
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