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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 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.

SUBMITTER: Stone ML

PROVIDER: S-EPMC8410039 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood. The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2-/-Il2rg-/- mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly. Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4+ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features-IL-23 and CD4+ Tems-that may have predictive potential for severe irAEs and ICIs response. Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.

Project description:Concomitant tumor necrosis factor (TNF) neutralization in combination with immune checkpoint inhibitors (ICIs) reduces clinical immune-related adverse events (irAEs) and appears to improve antitumor efficacy in preclinical tumor models. Agonistic antibodies targeting costimulatory receptors such as CD40 represent an additional strategy to boost antitumor immune response and potentiate the activity of ICIs. However, the dose-limiting toxicities observed in anti-CD40-treated cancer patients have hindered its clinical development. We previously described a mouse model to assess both antitumor activity and irAEs induced by various effective combination immunotherapies. Using the BALB/c and C57BL/6 strains of FoxP3-GFP-DTR (FoxP3DTR) mice, transient depletion of T regulatory cells (Tregs) prior to immunotherapy with additional immunomodulatory antibodies, lowered immune self-tolerance, resulting in the development of a spectrum of physical and biochemical irAEs similar to that reported clinically. In MC38 and 4T1.2 tumor models, following transient Treg depletion, we evaluated the impact of anti-CD40 on antitumor efficacy and the development of irAEs and the impact of concomitant or delayed TNF blockade on both these parameters. Physical irAEs were scored and biochemical irAEs were measured in the serum (ALT and cytokine levels). Histopathological liver and colon tissue analysis were performed to assess immune cell infiltration and tissue damage. Similar to early clinical trials of CD40 agonists, in our tumor models we observed liver toxicities and rapid release of proinflammatory cytokines (TNF, interleukin 6, interferon-γ). In the BALB/c strain, anti-CD40 induced severe physical and biochemical irAEs. Concomitant anti-TNF treatment abrogated weight loss, liver damage and colitis, which consequently resulted in an improved clinical score. However, concomitant anti-TNF impaired antitumor response in a proportion of anti-CD40-treated C57BL/6 FoxP3DTR mice. Delaying TNF blockade in these mice reduced biochemical but not physical irAEs while preserving antitumor efficacy. Our results suggest concomitant rather than delayed anti-TNF is most effective in reducing biochemical and physical irAEs induced by anti-CD40, although it had the potential to negatively impact antitumor efficacy. Furthermore, our findings highlight the utility of our mouse model to assess the severity of irAEs induced by novel immunotherapeutic agents and evaluate whether their toxicity and antitumor efficacy can be uncoupled.

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TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy.

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