Purpose: CD40 activation is a novel clinical opportunity for cancer immunotherapy. Despite numerous active clinical trials with agonistic CD40 monoclonal antibodies (mAb), biological effects and treatment-related modulation of the tumor microenvironment (TME) remain poorly understood.
Experimental design: Here, we performed a neoadjuvant clinical trial of agonistic CD40 mAb (selicrelumab) administered intravenously with or without chemotherapy to 16 patients with resectable pancreatic ductal adenocarcinoma (PDAC) prior to surgery followed by adjuvant chemotherapy and CD40 mAb.
Results: The toxicity profile was acceptable and overall survival was 23.4 months (95% CI 18.0 – 28.8). Based on a novel multiplexed immunohistochemistry platform, we report evidence that neoadjuvant selicrelumab leads to major differences in the TME compared to resection specimens from treatment-naive PDAC patients or patients given neoadjuvant chemotherapy/chemoradiotherapy only. For selicrelumab-treated tumors, 82% were T cell-enriched, compared to 37% of untreated tumors (p=0.004) and 23% of chemotherapy/chemoradiation-treated tumors (p=0.012). T cells in both the TME and circulation were more active and proliferative after selicrelumab. Tumor fibrosis was reduced, M2-like tumor-associated macrophages were fewer, and intratumoral dendritic cells were more mature. Inflammatory cytokines CXCL10 and CCL22 increased systemically after selicrelumab.
Conclusions: This unparalleled examination of CD40 therapeutic mechanisms in patients provides insights for design of subsequent clinical trials targeting this pathway.