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.

Elucidation of the Application of Blood Test Biomarkers to Predict Immune-Related Adverse Events in Atezolizumab-Treated NSCLC Patients Using Machine Learning Methods

“…The real challenge of irAE prediction is finding the right biomarkers to indicate the immune landscape in a spatial and temporal manner (8). In contrast to therapies with known biological mechanisms or specificity towards certain organs or tissue, targeting of the immune system by ICIs seems to have more unpredictable AEs, particularly irAEs that could potentially affect any part of the body.…”

“…In contrast to therapies with known biological mechanisms or specificity towards certain organs or tissue, targeting of the immune system by ICIs seems to have more unpredictable AEs, particularly irAEs that could potentially affect any part of the body. Nevertheless, research on intrinsic and extrinsic irAE mediators are taking place (8). As such, we reasoned that the prediction of irAEs involves two parallel options: (1) monitoring of immune activity and (2) malfunction detection in vulnerable organs or tissue.…”

Mechanisms of dermatological toxicities to immune checkpoint inhibitor cancer therapies

“…45 Caveats to these models are that some of the genetic changes in mice required to generate irAEs may not be applicable to human disease, and mouse microbiome changes associated with irAEs may not translate to human studies given the inherent differences between human and murine microbiota. 46…”

“…Noninvasive granzyme B‐targeted positron emission tomography imaging for visualizing irAEs identified changes in renal, colonic and splenic immune populations during ICI‐associated nephritis and colitis in Foxp3 ‐knockout mice 45 . Caveats to these models are that some of the genetic changes in mice required to generate irAEs may not be applicable to human disease, and mouse microbiome changes associated with irAEs may not translate to human studies given the inherent differences between human and murine microbiota 46 …”

Nanoengineering a metal–organic framework for osteosarcoma chemo-immunotherapy by modulating indoleamine-2,3-dioxygenase and myeloid-derived suppressor cells

“…In the tumor microenvironment (TME), functional immune cells, such as antigen-presenting cells, helper T (Th) cells and cytotoxic T lymphocytes (CTLs), are the workhorses for tumor cell clearance. Tumor cells can cooperate with suppressive immune cells, such as tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg), to create an immunosuppressive tumor microenvironment to resist functional immune cells [ 4 ]. Recently, the immunomodulatory effects of Gem have gradually been evaluated.…”