1. Introduction
cancer, tumor necrosis
CANCER, TUMOR NECROSIS, SOLID TUMORS, METASTATIC CANCER
CD40-targeting therapies can enhance the dendritic cell priming of tumor-specific T cells and repolarize intratumoral macrophages to alleviate the tumoral immunosuppressive environment and remodel the extracellular matrix. Mitazalimab is a potent agonistic CD40 monoclonal IgG1 antibody currently under clinical development. This study used RNA sequencing of blood samples from a subset of patients from a Phase I trial with mitazalimab (NCT02829099) to assess peripheral pharmacodynamic activity. We found that mitazalimab induced transient peripheral transcriptomic alterations (at 600 µg/kg and 900 µg/kg dose administered intravenously), which mainly were attributed to immune activation. In particular, the transcriptomic alterations showed a reduction in effector cells (e.g., CD8The advent of immune checkpoint inhibitors (ICIs) has profoundly transformed cancer therapy, offering a potential remedy for individuals with advanced or metastatic cancer [CD40, a member of the tumor necrosis factor receptor superfamily, is expressed on the surface of immune cells (e.g., dendritic cells (DCs), B cells, and macrophages) as well as on other cell types such as epithelial, endothelial, and neoplastic cells [Mitazalimab, a CD40-targeting agonistic human monoclonal IgG1 antibody (mAb), is being developed as immunotherapy for advanced solid tumors. Preclinically, mitazalimab has shown significant antitumor activity and long-term tumor-specific immunity in human CD40-transgenic mice as well as antitumor activity in immune-deficient NSG mice [In this study, the peripheral transcriptome of a subset of patients from a Phase I clinical study of mitazalimab (NCT02829099) was explored for pharmacodynamic activity. We found that mitazalimab transiently induces peripheral transcriptomic changes attributed to immune activation, reinforcing its mode of action as a CD40 agonist. Furthermore, the transcriptomic data enabled patient stratification, unveiling distinct alterations induced by mitazalimab in two different patient groups.