Journal-Based CME: Intestinal Toxicity to CTLA-4 Blockade Driven by IL-6 and Myeloid Infiltration

This Journal-Based CME activity consists of a full-text article that is free to read, a multiple-choice question test, and an evaluation/self-assessment. Learners are tested on their comprehension of the key concepts, with the objective of enriching their clinical practice and patient care through better understanding of scientific advances and new techniques in the fields covered by Journal of Experimental Medicine (JEM).

Questions for this complimentary, online-only activity have been designed by JEM editors in collaboration with the article authors. Each CME activity should take approximately 1 hour to complete.

The article selected for this activity is Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration by Yifan Zhou, Stephanie S. Watowich, of the University of Texas MD Anderson Cancer Center, and colleagues.

Article Abstract

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (aCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found aCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of aCTLA-4–mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved aCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of aCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

About Journal of Experimental Medicine (JEM) and CME Activities

JEM publishes peer-reviewed papers within the field of medical biology, providing novel conceptual insights into immunology, cancer biology, neuroscience, inflammation, vascular biology, microbial pathogenesis, and stem cell biology. These studies range from original findings on all aspects of disease pathogenesis to novel therapeutic approaches. Articles designated for Journal-Based CME have been selected by JEM editors for their clinical relevance and ability to address practice-based gaps.

1. Comprehend key points in the research findings outlined in the activity.
2. Differentiate between old and new concepts.
3. Learners will have the information necessary to apply the relevant points to their clinical practice.

Memorial Sloan Kettering Cancer Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

AMA Credit Designation Statement

Memorial Sloan Kettering Cancer Center designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Recorded/Review Date: November 8, 2022 | Original Release Date: November 8, 2022 | Termination Date: November 8, 2025

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