Title: Preparing for a Phase I/II clinical trial of autologous T cell gene therapy to treat X-linked lymphoproliferative disease (XLP)
Funder: LifeArc

Abstract: X-linked lymphoproliferative disease (XLP) is a rare genetic condition that affects boys. Symptoms vary but most patients have abnormal immune responses to some viral infections (called haemophagocytic lymphohistiocytosis or HLH). These can result in rapid death. They also often experience recurrent infections and about a third develop lymphoma. Affected boys become sick in childhood or early adolescence. Patients are often treated with lifelong immunoglobulin therapy. Bone marrow transplants can be effective as a treatment but the results depend on whether the transplant takes place before any symptoms develop, as well as having a well-matched donor. Up to half of patients who receive a transplant from a mismatched donor with active disease will not survive. There is a clear unmet need for patients who do not have a suitable transplant donor. Alternative approaches are required to reduce the burden of disease complications, avoid regular immunoglobulin therapy and reduce the risks of malignancy and HLH. Dr Booth’s approach would offer a cost benefit over bone marrow transplant, which typically costs more than £250,000 and even more if patients develop transplant-related complications. Most of the immune system abnormalities seen in this condition arise due to abnormal function of T-cells. The team had already shown, using an XLP mouse model and through studies on XLP patient T-cells, that some of the abnormalities could be corrected by using gene-corrected T-cells. The benefits include improved immunoglobulin production and antibody responses to immune challenge and tumour formation. The team therefore believes that gene therapy correcting patients’ T-cells will help many of their symptoms and may be a safer treatment option than a bone marrow transplant from an unrelated donor. Using the patient’s own cells avoids any risk of graft versus host disease – which can cause significant morbidity and mortality after transplant. With less chemotherapy required, this approach would reduce toxicity associated with the procedure. As in other gene therapy clinical trials underway at UCL Great Ormond Street Institute of Child Health, this project uses a type of virus (a lentivirus) to transfer a normal copy of the defective gene into patient T-cells. There have been no safety concerns associated with this type of virus or infusing patients with gene modified T-cells (for example to treat specific forms of cancer). The research aims to reach the clinical trial stage, offering patients lacking a suitable donor for bone marrow transplant an alternative treatment. The funding supports generating and testing the virus for clinical use, undertaking the required safety and efficacy studies and ensuring the appropriate regulatory framework is in place to initiate a Phase I/II clinical trial at Great Ormond Street Hospital. This is the first trial of its kind for XLP and the T-cell gene therapy approach could be used to treat other immune disorders affecting T-cells. UCL Great Ormond Street Institute of Child Health has extensive experience of translating and delivering successful gene therapy trials for immune disorders and the treatment, if effective, will be taken forwards to a pivotal (phase III) registration trial so the therapy can be licensed and made more widely available.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;6.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM