TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy

Abstract

Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for anti-tumor 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 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 interleukin (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 anti-tumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.

The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota

“…Depleting macrophages or neutrophils or blocking TNFα production was sufficient to prevent anti-CD40 induced liver damage, which is consistent with previous reports. 41 , 53 , 54 , 55 , 56 Our study adds to these previous reports by demonstrating that the gut microbiota is critically required for anti-CD40-induced pathogenic immune cell infiltration/activation in the liver and for anti-CD40-induced cytokine release. While both macrophages and neutrophils were required for anti-CD40-induced liver damage, only macrophage depletion reduced anti-CD40-induced systemic TNFα release.…”

Cancer immunotherapy via synergistic coactivation of myeloid receptors CD40 and Dectin-1

“…S2, D and E). In addition, combination treatment showed no evidence of increased rates of cytokine release syndrome or hepatotoxicity ( 30 ), which are common adverse events with aCD40 (fig. S2, F and G).…”

“…BE0016-2; RRID: AB_1107647; 0.1 mg) was administered on day 0. Mice (~5%) that did not show depletion of CD19 + B cells at 24 hours after treatment with anti-CD40 were excluded as previously described ( 30 ). For T cell depletion, anti-CD4 (clone GK1.5; catalog no.…”

FcγRs and Their Relevance for the Activity of Anti-CD40 Antibodies

“…In this respect, it is worth mentioning that preclinical studies have shown that the intratumoral and systemic application of anti-CD40 antibodies is therapeutically equally effective, but that local application in the tumor is associated with fewer side effects [ 105 , 106 , 107 , 108 , 109 ]. Moreover, a recent study showed that TNF inhibition prevented the hepatotoxicity triggered by combined treatment with an anti-CD40 antibody and gemcitabine without affecting antitumor activity [ 110 ]. Thus, the maximal exploitation of potent autonomous CD40 agonists for tumor therapy may require defined treatment regimens that restrict the antibody activity to the tumor area and/or systemically inhibit CD40 effector molecules.…”