CD40 agonist-induced IL-12p40 potentiates hepatotoxicity

Abstract

BackgroundCD40 is a compelling target for cancer immunotherapy, however, attempts to successfully target this pathway have consistently been hampered by dose-limiting toxicity issues in the clinic that prevents the administration of efficacious doses.MethodsHere, using cytokine and cytokine receptor depletion strategies in conjunction with a potent CD40 agonist, we investigated mechanisms underlying the two primary sources of CD40 agonist-associated toxicity, hepatotoxicity and cytokine release syndrome (CRS).ResultsWe demonstrate that CD40 agonist -induced hepatotoxicity and CRS are mechanistically independent. Historical data have supported a role for interleukin-6 (IL-6) in CRS-associated wasting, however, our findings instead show that an inflammatory cytokine network involving TNF, IL-12p40, and IFNγ underlie this process. Deficiency of TNF or IFNγ did not influence CD40-induced hepatitis however loss of IL-12p40 significantly decreased circulating concentrations of liver enzymes and reduced the frequency of activated CD14+MHCII+myeloid cells in the liver, indicating a role for IL-12p40 in liver pathology.ConclusionsAs clinical research programs aim to circumnavigate toxicity concerns while maintaining antitumor efficacy it will be essential to understand which features of CD40 biology mediate antitumor function to develop both safe and efficacious agonists.

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

“…Anti-TNF- prevented body weight loss triggered by aCD40 (fig. S20A), in accordance with previous observations (14), and abrogated liver necrosis (Fig. 7D).…”

Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies

“…Notably, at the 2-fold systemic MTD dose, hydrogel delivery led to significantly lower serum levels of key proinflammatory cytokines, including IFNy, TNFa, IL12, and CXCL10. In particular, the reduction in systemic IL12 may be critical for attenuating CD40-agonist mediated hepatotoxicity (46). While CD40a hydrogels appeared to suppress systemic cytokine induction, these hydrogels mediated significantly higher levels of effector cytokines in the TdLN compared to systemic administration methods.…”

“…In particular, the reduction in systemic IL12 may be critical for attenuating CD40-agonist mediated hepatotoxicity. [28] By assessing cytokine induction at varying CD40a dose with both hydrogel and local bolus administration, we identified that drug delivery strategy determined dose-response behavior for peripheral cytokines. In particular, hydrogels reduced systemic cytokine levels by either altering the slope or the elevation of individual cytokine dose-response curves.…”

Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

“…The interaction of CD40 with its ligand (CD40L) or agonistic anti-CD40 mAbs also promotes the production of TNF-α, ROS and NO [ 165 ] in macrophages, which can all potentially enhance ADCP. Furthermore, in response to treatment with agonistic anti-CD40 mAbs in pre-clinical models, macrophages secrete IL-12, which is essential for the induction of the antitumor Th1 phenotype [ 166 ]. Using the LSL-Kras G12D/+ ;LSL-Trp53 R172H/+ ;Pdx-1-Cre (KPC) model of pancreatic ductal adenocarcinoma, Beatty et al observed that macrophages activated with an agonistic anti-CD40 mAb rapidly infiltrated tumors, participated in cancer cell killing, and facilitated the depletion of the tumor stroma.…”

“…To date, several anti-CD40 mAbs have been investigated in clinical trials ( Table 1 ), either as single agents or in combination with chemotherapy or checkpoint inhibitor therapy. Although these reagents have shown promise in inducing tumor regression or stabilizing disease, severe adverse events, including cytokine release syndrome and hepatotoxicity, have limited their clinical development [ 166 ]. Nonetheless, there has been a concerted interest in developing anti-CD40 mAb therapies that induce potent antitumor responses in patients.…”