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.
Highlights
Most patients with solid cancers do not respond to T cell immunotherapies [1]
Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity
Preclinical modeling shows that myeloid agonists can enhance the therapeutic potential of T cell immunotherapy by triggering the activation of antigen-presenting cells (APCs) that are critical for the priming of antitumor T cell responses [2,3,4,5]
Summary
Preclinical modeling shows that myeloid agonists can enhance the therapeutic potential of T cell immunotherapy by triggering the activation of antigen-presenting cells (APCs) that are critical for the priming of antitumor T cell responses [2,3,4,5]. In this regard, CD40 is a member of the TNF receptor superfamily and is expressed by APCs, including DCs. When ligated, CD40 “licenses” DCs with the capacity to prime T cells in an antigen-specific manner [6,7,8]. CD40 has emerged as a promising target for cancer immunotherapy
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