TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy

Area of Science:

• Immunology
• Hepatology
• Oncology

Background:

• Agonist CD40 antibodies are investigated with chemotherapy to enhance anti-tumor T cell immunity.
• Anti-CD40 therapy often causes cytokine release and elevated liver enzymes, leading to dose-limiting toxicities.
• Anti-CD40 treatment can exacerbate chemotherapy-induced liver injury (hepatotoxicity).

Purpose of the Study:

• To elucidate the mechanism linking anti-CD40-induced cytokine release and chemotherapy-induced hepatotoxicity.
• To identify strategies for mitigating anti-CD40-related toxicities without compromising anti-tumor efficacy.

Main Methods:

• Investigated the effects of anti-CD40 in combination with chemotherapy in mouse models and human subjects.
• Utilized transcriptional profiling of liver tissue to identify activated cytokine pathways.
• Administered neutralizing antibodies against TNF and IL-6 to assess their impact on toxicity and efficacy.

Main Results:

• Anti-CD40 antibodies induce transient hepatotoxicity and sensitize the liver to drug-induced injury.
• This sensitization was not abrogated by depleting myeloid cell subsets.
• Transcriptional analysis revealed activation of TNF and IL-6 pathways.
• Neutralization of TNF, but not IL-6, prevented liver sensitization without impairing anti-tumor efficacy.

Conclusions:

• A mechanistic link exists between anti-CD40-induced cytokine release and chemotherapy-induced hepatotoxicity.
• Targeting TNF offers a clinically feasible strategy to mitigate liver toxicity associated with anti-CD40 immunotherapy combined with chemotherapy.
• This approach preserves the therapeutic anti-tumor immune response.