Phase I study of B7-H3 targeting CAR-T cells administered by local delivery in paediatric high risk brain tumour patients.
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
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.
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.
Technical Summary
Chimeric Antigen Receptor have become a forefront experimental treatment strategy in haemato-oncology. Paediatric brain tumours present a major unmet due to lack of treatment options for recurrent disease and for some forms of primary disease, compounded by the challenge of optimally delivering therapeutic agents to the tumour site.
We propose that a rational solution is locoregional delivery of CAR-T cells into the CSF of children with relapsed refractory brain cancer. This holds the prospect of limiting systemic toxicity whilst focussing the treatment to the site of disease. To this end we have generated a chimeric antigen receptor (TE9-28Z-iTAG2) recognising the tumour antigen B7-H3, which is highly expressed on paediatric brain tumours whilst largely absent from healthy brain. TE9-28Z-iTAG2 is a novel and regulatable CAR-T technology with capability to eradicate established tumours using locoregional delivery. The iTAG2 degrader tag technology allows reversible downregulation of CAR expression in two settings; 1) during manufacture, which limits tonic signaling and T cell exhaustion, and 2) following administration, which is a potential therapeutic strategy for reversing tumour-induced T cell exhaustion. We therefore propose a phase I trial in children with relapsed high risk brain tumours, in which autologous TE9-28Z-iTAG2 CAR-T will be administered into the ventricles via an indwelling catheter without preconditioning lymphodepleting chemotherapy. Repeat infusions will be scheduled to maximise potential for clinical responses. Repeat infusions and the use of the iTAG2 mediated CAR off-switch during manufacture will help maintain and consolidate clinical responses. The primary objective is to determine the maximum tolerated dose of T cells. Secondary endpoint will be extent and duration of clinical responses. Exploratory endpoints will be collection of longitudinal samples for CAR-T functional phenotype and T cell dysfunction mechanisms.
We propose that a rational solution is locoregional delivery of CAR-T cells into the CSF of children with relapsed refractory brain cancer. This holds the prospect of limiting systemic toxicity whilst focussing the treatment to the site of disease. To this end we have generated a chimeric antigen receptor (TE9-28Z-iTAG2) recognising the tumour antigen B7-H3, which is highly expressed on paediatric brain tumours whilst largely absent from healthy brain. TE9-28Z-iTAG2 is a novel and regulatable CAR-T technology with capability to eradicate established tumours using locoregional delivery. The iTAG2 degrader tag technology allows reversible downregulation of CAR expression in two settings; 1) during manufacture, which limits tonic signaling and T cell exhaustion, and 2) following administration, which is a potential therapeutic strategy for reversing tumour-induced T cell exhaustion. We therefore propose a phase I trial in children with relapsed high risk brain tumours, in which autologous TE9-28Z-iTAG2 CAR-T will be administered into the ventricles via an indwelling catheter without preconditioning lymphodepleting chemotherapy. Repeat infusions will be scheduled to maximise potential for clinical responses. Repeat infusions and the use of the iTAG2 mediated CAR off-switch during manufacture will help maintain and consolidate clinical responses. The primary objective is to determine the maximum tolerated dose of T cells. Secondary endpoint will be extent and duration of clinical responses. Exploratory endpoints will be collection of longitudinal samples for CAR-T functional phenotype and T cell dysfunction mechanisms.
