Developing novel therapeutics and biomarkers to promote and monitor the health and longevity of transplanted organs, reducing the dependency on immune suppression drugs
Transplantation of a solid organ such as kidney, liver or heart, is a life-saving surgical technique for organ failure but requires life-long immunosuppression to avoid rejection which poses the risk of side effects, cancer and infection. The goal of the Transplantation Theme is to develop novel therapeutics and biomarkers to promote and monitor the health and longevity of transplanted organs, reducing the dependency on immune suppression drugs. We have pioneered the use of T-reg cell therapies and biologics to block complement activation and these are now in clinical development to prevent early inflammation and oppose immune-mediated rejection. By analysing many longitudinal blood samples, our biomarker researchers are advancing non-invasive monitoring strategies that can predict acute rejection before clinical signs are apparent and at a time when giving stronger immunosuppression may still be effective. Similarly, signals of functional tolerance will allow safer tapering of immunosuppression and provide mechanistic insight into the fine balance of rejection versus tolerance.
Our work is divided across four programmes:
- Programme 1. Novel inhibitors of complement and early inflammation
- Programme 2. Regulatory T cell Therapy
- Programme 3. Biomarkers and immune monitoring of rejection
- Programme 4. Imaging immunity – tracking cell therapies and imaging complement.
- Regulatory T cells as advanced therapies for organ transplantation Transplantation is the gold standard treatment for patients with organ failure. However, organ transplant recipients require life-long immunosuppression to avoid rejection which poses risk of side effects, cancer and infection. A way to counteract rejection is by increasing the number of a small subset of immune cells, called regulatory T cells or T-regs, that have potent anti-inflammatory properties. This can be achieved by isolating T-regs from blood, growing them in large numbers in the laboratory, and re-infusing them into transplant patients. Building on our expertise in developing GMP-grade T-reg manufacturing to reduce immunosuppressant burden in renal (ONE study) and liver transplantation (ThRIL study – Sanchez-Fueyo A et al. (2020), Am J Transplant 20(4):1125-1136) a new KCL spin-out company, Quell Therapeutics, will use genetic engineering technologies such as the CAR (chimeric antigen receptor) to modify the patient’s own T-regs to treat diseases caused by uncontrolled inflammation for which there are currently no effective treatments. As the first indication, Quell is sponsoring a clinical trial that will be performed in collaboration with the BRC, in which liver transplant patients will receive CAR-T-regs recognizing the transplanted liver. In kidney transplantation, just over a third of patients awaiting a transplant are ‘highly sensitised’ to human leukocyte antigens (HLA), resulting in circulating HLA antibodies (Ab). These Ab reduce the chance of receiving an organ, as organs are only offered when no Ab is present. In a new clinical trial (GAMECHANgER-1) we are exploring whether T-regs can suppress the immune responses against these Abs, as part of a novel strategy to improve rejection-free survival and outcomes for sensitised patients.
- Non-invasive diagnosis of tranplant rejection A development of a reliable non-invasive diagnostic test capable of distinguishing early stages in the development of rejection is a significant unmet medical need in organ transplantation. In the Kidney ALograft Immune Biomarkers of REjection (KALIBRE) study, we identified a signature of gene expression from seven genes that corellates with acute kidney rejection. Importantly the gene signature became positive up to seven weeks before the diagnostic biopsy (Christakoudi S et al. (2019) EBioMedicine. 41, 571-583). There is, therefore, an increasing body of evidence that biomarkers in blood can aid in the management of patients post renal transplant and we are planning further work to bring these into the clinical setting. Likewise, in liver transplantation, we have developed non-invasive markers to identify adult or paediatric transplant recipients with active sub-clinical rejection (Vionnet J et al. (2021) J of Hepatol 75, 1409-1419). These markers will be employed to select transplant recipients likely to benefit from immunosuppression minimisation strategies.