TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy

JCI Insight. 2021 Jul 22;6(14):e146314. doi: 10.1172/jci.insight.146314.


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.

Keywords: Cancer immunotherapy; Cytokines; Immunology.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • CD40 Antigens / agonists*
  • CD40 Antigens / immunology
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / immunology
  • Cell Line, Tumor
  • Chemical and Drug Induced Liver Injury / immunology
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Humans
  • Immunotherapy / methods
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / metabolism
  • Liver / drug effects
  • Liver / immunology
  • Liver / pathology
  • Mice
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • CD40 Antigens
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • selicrelumab