Time to dissect the autoimmune etiology of cancer antibody immunotherapy

J Clin Invest. 2020 Jan 2;130(1):51-61. doi: 10.1172/JCI131194.

Abstract

Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory "checkpoint" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antibodies, Monoclonal / adverse effects*
  • Antineoplastic Agents, Immunological / adverse effects*
  • Autoimmune Diseases / chemically induced*
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / physiology
  • Endocrine System Diseases / chemically induced
  • Humans
  • Immunotherapy / adverse effects*
  • Inflammatory Bowel Diseases / chemically induced
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / physiology
  • Tumor Microenvironment / drug effects

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents, Immunological
  • CTLA-4 Antigen
  • Programmed Cell Death 1 Receptor