NOVEL HUMORAL AND CELLULAR BIOMARKERS OF AUTOIMMUNE DISEASES CAUSED BY IMMUNOTHERAPY
NIH
BAYLOR COLLEGE OF MEDICINE
Immunotherapy has transformed the treatment landscape for a wide range of human malignancies. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block the immune regulatory “checkpoint” receptors, the Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), Programmed Cell Death 1 (PD-1), or its ligand PD- L1. ICIs produce durable responses in many patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs), such as diabetic ketoacidosis (DKA) or thyroid disease, appearing to occur more frequently than originally expected. Immunotoxicity from cancer immunotherapy occurs in up to 90%, whereas autoimmune endocrine diseases occur in approximately 50% of patients treated with antibodies to CTLA-4 and/or PD-1/PD-L1. These irAEs can be serious or even life- threatening, such as autoimmune type 1 diabetes (T1D) presenting in DKA, and primary adrenal insufficiency caused by autoimmune adrenalitis. A recent study showed a marked increase of ICI-related autoimmune diabetes; reported in over 50% of the patients, with half of these patients presenting in DKA (50.2%). Thus, reliable biomarkers are needed to accurately stratify the risk of irAEs in patients who are candidates for these therapies (Aim I); these biomarkers may point to novel molecular pathways that could be targeted to prevent irAEs caused by immune checkpoint blockade (Aim II). Specifically, we will utilize the state-of-the-art single-cell platforms to investigate and characterize the comprehensive phenotypic and functional analyses of systemic cellular networks in patients with ICI-induced endocrinopathies. Our studies are greatly facilitated by the Baylor College of Medicine Immunotoxicity Working Group. Understanding the immunologic factors and the biomarkers associated with ICI-mediated inflammatory toxicities will be useful for the identification and early treatment of ICI-induced irAEs, and it may provide new insights into the pathoetiology and treatment of autoimmune endocrine diseases. PROJECT NARRATIVE Immune checkpoint inhibitors can result in long-lasting clinical responses in a variety of advanced or metastatic malignancies, but approximately half of patients receiving these drugs develop autoimmune endocrinopathies. Our proposal brings together expertise in three complementary areas such as endocrinology, autoimmunity, and oncology. The outcome of this investigation will provide mechanistic insights into immunotherapy-related adverse events and may provide the groundwork for understanding how to limit the toxicity of immunotherapy as well as improving treatments of autoimmune endocrine diseases.
Non-SBIR/STTR