Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy
Meredith L. Stone, … , Kristen B. Long, Gregory L. Beatty
Meredith L. Stone, … , Kristen B. Long, Gregory L. Beatty
Published June 8, 2021
Citation Information: JCI Insight. 2021;6(14):e146314. https://doi.org/10.1172/jci.insight.146314.
View: Text | PDF
Research Article Immunology

TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy

  • Text
  • PDF
Abstract

Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.

Authors

Meredith L. Stone, Jesse Lee, Veronica M. Herrera, Kathleen Graham, Jae W. Lee, Austin Huffman, Heather Coho, Evan Tooker, Max I. Myers, Michael Giannone, Yan Li, Thomas H. Buckingham, Kristen B. Long, Gregory L. Beatty

×

Figure 4

TNF blockade inhibits hepatotoxicity due to chemoimmunotherapy without affecting treatment efficacy.

Options: View larger image (or click on image) Download as PowerPoint
TNF blockade inhibits hepatotoxicity due to chemoimmunotherapy without a...
(A) Study schema used in B–D. Shown are (B) mean mouse weights over time, (C) overall survival, and (D) mean tumor growth curves. Statistical significance was determined using the following tests: in B, ordinary 1-way ANOVA with Dunnett’s multiple-comparison test was performed on weights on day 2; in C, Mantel-Cox test was used; and in D, Kruskal-Wallis with Dunn’s multiple-comparison test was performed on tumor volume on day 44. n = 10 mice/group. Data are representative of n = 2 experimental replicates. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts