Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR

Abstract

Recent advances in cancer immunotherapy have completely revolutionized cancer treatment strategies. Nonetheless, the increasing incidence of immune-related adverse events (irAEs) is now limiting the overall benefits of these treatments. irAEs are well-recognized side effects of some of the most effective cancer immunotherapy agents, including antibody blockade of the cytotoxic T-lymphocyte-associated protein 4 and programmed death protein 1/programmed-death ligand 1 pathways. To develop an action plan on the key elements needed to unravel and understand the key mechanisms driving irAEs, the Society for Immunotherapy for Cancer and the American Association for Cancer Research partnered to bring together research and clinical experts in cancer immunotherapy, autoimmunity, immune regulation, genetics and informatics who are investigating irAEs using animal models, clinical data and patient specimens to discuss current strategies and identify the critical next steps needed to create breakthroughs in our understanding of these toxicities. The genetic and environmental risk factors, immune cell subsets and other key immunological mediators and the unique clinical presentations of irAEs across the different organ systems were the foundation for identifying key opportunities and future directions described in this report. These include the pressing need for significantly improved preclinical model systems, broader collection of biospecimens with standardized collection and clinical annotation made available for research and integration of electronic health record and multiomic data with harmonized and standardized methods, definitions and terminologies to further our understanding of irAE pathogenesis. Based on these needs, this report makes a set of recommendations to advance our understanding of irAE mechanisms, which will be crucial to prevent their occurrence and improve their treatment.

Keywords: autoimmunity; immunotherapy; translational medical research.

Figure 1

Future directions for irAE research. Effective clinical modeling of irAEs will require the integration of a variety of data, including: (1) standardized definitions of irAEs and tools to identify them, (2) clinical data from electronic health records that reflect the critical components of irAEs and cancer descriptions and outcomes that have been standardized using common data models to support data sharing, (3) collaborative biospecimen biobanking programs with standardized operating procedures for tissue collection, processing and storage, and (4) high-quality, high-throughput multiomics, proteomics and immunophenotyping data integration strategies that provide mechanistic information. The overall clinical modeling of irAE disease pathogenesis efforts will require multidisciplinary clinicians and scientists and the development of modeling, management and analysis strategies and data collection from a large number of organizations to represent the wide range of irAEs, particularly rare irAEs. Clinical modeling will also require data storage technologies that support integration of clinical and mechanistic data while preserving participant privacy and novel machine learning strategies to derive insights about risk factors and biomarkers of disease that can lead to new diagnostics and therapeutics for clinical care as well as support refinement and development of more effective preclinical models. irAE, immune-related adverse event.