Phase I/II clinical trial of autologous T cell gene therapy to treat X-linked lymphoproliferative disease (XLP)

X-linked lymphoproliferative disease (XLP) is a rare genetic condition that affects boys. Symptoms vary but most patients have dangerous immune responses to some viral infections (called haemophagocytic lymphohistiocytosis or HLH), recurrent infections and about a third develop lymphoma. Affected boys become sick in childhood or early adolescence. At the moment, patients are often treated with lifelong immunoglobulin therapy and treatment of any malignancies or disease complications. We can offer bone marrow transplant as a treatment, but the results depend on having a well-matched donor and preferably transplant before complications develop. Up to 50% of patients with active disease transplanted from a mismatched donor will not survive after transplant. There is a clear unmet need for patients lacking a suitable transplant donor and alternative approaches are required to alleviate the burden of disease complications, prevent infections lifelong and reduce risks of malignancy and HLH. Most of the immune system abnormalities seen in this condition arise due to abnormal function of T cells. We have already shown using an XLP mouse model and through studies on XLP patient T cells that we can correct many of these abnormalities including immunoglobulin production, antibody responses to immune challenge and tumour formation through providing gene corrected T cells. We therefore believe that gene therapy of patients' T cells alone will help many of their symptoms and may be a safer treatment option than a bone marrow transplant from an unrelated donor. By using the patient's own cells we avoid any risk of graft versus host disease which can cause significant morbidity and mortality after transplant and we are able to use less chemotherapy than would be involved in a bone marrow transplant. As in other gene therapy clinical trials underway in our department, we will use 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 aim of this proposal is an early-phase clinical trial of T cell gene therapy which may offer XLP patients a long-term treatment option. We seek funding to generate and test virus suitable for clinical use and perform a clinical trial at Great Ormond Street Hospital recruiting 7 patients. We plan to include patients over 1-year-old and under 18 years of age with a confirmed diagnosis of XLP. T cells will be collected, corrected and frozen to ensure we have sufficient gene-corrected cells to give back to the patient. Patients will be monitored to establish the safety and efficacy of the treatment focusing on the detection of gene-corrected cells and the ability to stop immunoglobulin therapy without infection risk. This will be the first trial of its kind for XLP and the T cell gene therapy approach outlined could be used to treat other immune disorders affecting T cells. We have extensive experience in delivering successful gene therapy trials for immune disorders and if we can show that this treatment is effective we will undertake a pivotal registration trial allowing a move towards licensing which would make this therapy more widely available.