RISE: Reducing Immune Stress from Excess cytokine release in advanced therapies

Immunotherapy has significantly improved survival outcomes for patients with cancer. Advanced therapies (ATs), including chimeric antigen receptor (CAR)-T, T-cell receptor (TCR-T) and tumour-infiltrating lymphocyte (TIL) therapies, have demonstrated promising results for haematological and solid malignancies. To date, eight cell therapies have received US FDA approval, with two CAR-T (leukaemia/lymphoma) NHS-funded. Despite this, barriers persist in wider use of ATs. Patients receiving CAR-T encounter significant concerns regarding accessibility/logistics and long-term safety. Contemporary post-approval experience with immune-checkpoint inhibitors highlights a research bias toward efficacy over safety, in part due to underfunding of mechanistic studies on immunotherapy-related adverse events. This has resulted in predominantly reactive versus preventative/proactive patient management strategies. Adverse events associated with T-cell-specific ATs are dominated by cytokine release syndrome (CRS), with up to 22% classified as severe, potentially requiring intensive care. Other serious clinical manifestations include immune effector cell-associated neurotoxicity syndrome (ICANS), haemophagocytic lymphohistiocytosis (HLH), and macrophage activation syndrome (MAS). Further complications e.g. coagulopathy, prolonged cytopenias and infections, can result in extended hospitalisation, psychological distress and significant caregiver burden. Despite these challenges, there is a lack of comprehensive guidance on long-term pharmacovigilance. Following consultation with expert patient and public voice partners (PPVPs) (ATMP Engage), we developed RISE, a multidisciplinary public-private consortium dedicated to facilitating safe and efficient clinical adoption of ATs. RISE leverages NHS and academic expertise within Manchester’s ecosystem, supported by four UK-based business partners (Poolbeg Pharma, Pfizer, Sanius, Randox) contributing >£2 million in cash and >£2 million 'in-kind', to integrate discovery science and translational research to enhance patient outcomes. RISE will employ scalable technology platforms to profile n=80-100 patients receiving standard-of-care CAR-T through a prospective observational clinical study. Concurrently, our main business partner Poolbeg Pharma will fund the translational endpoints of a Phase 1/2 trial (n=30-40 patients) investigating POLB001, a novel CRS-prevention agent. Leveraging MCRC Biobank and existing governance frameworks, we will collect and analyse longitudinal blood samples for high-dimensional immunoprofiling, bulk RNA-sequencing of PBMCs (including TCR/BCR repertoire analysis and T-cell fitness assessment), and point-of-care cytokine testing. Bone marrow spatial profiling and stool microbiome analysis will further elucidate toxicity mechanisms. Additionally, RISE will integrate expertise from the Manchester Wearables Research Group, Sanius, and The Christie Patient-Centred Research Team to develop tools for long-term safety monitoring. Wearables will provide continuous inpatient and post-discharge tracking, complemented by AT-specific patient-reported outcome measures (PROMs) for real-time toxicity assessment. Finally, we will work closely with experts from University of Manchester’s computational and data science teams, including Christabel Pankhurst Institute, to deliver on multimodal data integration. To compliment our strategy and robustness of key findings, we will employ artificial intelligence and machine learning approaches to create digital twins and virtual cohorts, simulating diverse hypothetical trajectories in patient outcomes. In summary, RISE represents an ambitious, interdisciplinary programme to improve AT safety and efficacy. Through cross-sector collaboration, technology integration and patient-centred approaches, we aim to establish new standards for AT development, regulation and implementation. Our long-term vision includes expanding RISE into a UK-wide network and serving as an exemplar blueprint for attracting further industry investment. With consortium members already actively engaged with ATTC, MHRA and NICE, we anticipate that RISE will further contribute to regulatory efforts and shape guidelines for safer AT deployment. We will establish an open-access toxicity database to support further research and collaborate with PPVPs to further build expertise in this evolving field.