Defining biomarkers and mechanisms of cancer immunotherapy toxicity

Cancer immunotherapy has revolutionized the treatment of many cancers, but this potentially effective treatment can also cause significant side-effects. Treatment-related toxicities result from non-specific activation of the immune response, leading to the unmasking or initiation of autoimmune phenomena; for this reason, they are called "immune-related adverse events", or "irAE". The mainstay of management for these toxicities is immunosuppression with anti-inflammatory steroids (glucocorticoids) and in severe, steroid-resistant cases, more aggressive immunosuppressive agents such as infliximab. These treatments have their own drawbacks, and are likely excessively broad in their action. Surprisingly little is known about the specific mechanisms involved in irAE, partly because of the sheer diversity of toxicities that can occur, affecting potentially any body organ or system. Similarly, no current methods exist to predict who will experience irAE, let alone what type or how severe. This project aims to improve the prediction and management of irAE in cancer patients by first identifying the underlying characteristics of a toxicity-prone immune system before toxicity occurs. We have previously performed extensive multi-platform immune, genomic, and microbial analyses in immunotherapy treated melanoma patients aiming to identify biomarkers of immunotherapy response and toxicity [1]. We will extend upon these studies using a combination of patient-derived samples and pre-clinical models to systematically evaluate irAE biomarkers across multiple domains, including: - circulating adaptive and innate immune cell populations - blood-based antibody profiles and metabolites - genomic correlates In parallel, laboratory studies will explore the mechanisms that drive common types of irAE, and explore the interactions between cancer immunotherapy and co-administered immunosuppressive agents that are used in the clinic to treat irAE including combinatorial screening of immunomodulators in ex vivo tumour fragment cultures systems. 1. Nat Med. 2021 Aug;27(8):1432-1441. doi: 10.1038/s41591-021-01406-6.