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Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with
Katelyn T Byrne1,2, Courtney B Betts3,4, Rosemarie Mick1,5
1Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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.
Patients And Methods:
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) before surgery followed by adjuvant chemotherapy and CD40 mAb.
Results:
The toxicity profile was acceptable, and overall survival was 23.4 months (95% confidence interval, 18.0-28.8 months). Based on a novel multiplexed immunohistochemistry platform, we report evidence that neoadjuvant selicrelumab leads to major differences in the TME compared with resection specimens from treatment-naïve PDAC patients or patients given neoadjuvant chemotherapy/chemoradiotherapy only. For selicrelumab-treated tumors, 82% were T-cell enriched, compared with 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/sec CXCL10 and CCL22 increased systemically after selicrelumab.
Conclusions:
This unparalleled examination of CD40 mAb therapeutic mechanisms in patients provides insights for design of subsequent clinical trials targeting CD40 in cancer.
Insights
Agonistic CD40 monoclonal antibodies (mAb) like selicrelumab show promise in cancer immunotherapy by enriching tumors with T-cells and enhancing their activity. This approach modulates the tumor microenvironment, offering new insights for future clinical trials.
Area of Science:
- Immunology
- Oncology
- Clinical Trials
Background:
- CD40 activation presents a novel strategy for cancer immunotherapy.
- Clinical trials using agonistic CD40 monoclonal antibodies (mAb) are ongoing, but their biological effects and impact on the tumor microenvironment (TME) are not fully understood.
Purpose of the Study:
- To investigate the biological effects of neoadjuvant agonistic CD40 mAb (selicrelumab) on the tumor microenvironment (TME) in patients with pancreatic ductal adenocarcinoma (PDAC).
Main Methods:
- A neoadjuvant clinical trial involving 16 patients with resectable PDAC treated with selicrelumab, with or without chemotherapy, before surgery.
- Utilized a novel multiplexed immunohistochemistry platform to analyze tumor specimens and peripheral blood.
Main Results:
- Neoadjuvant selicrelumab treatment resulted in T-cell enrichment in 82% of tumors, compared to 37% in untreated and 23% in chemotherapy-treated tumors.
- Observed increased T-cell activity and proliferation, reduced tumor fibrosis, decreased M2-like macrophages, and enhanced dendritic cell maturation.
- Systemic increases in inflammatory cytokines CXCL10 and CCL22 were noted post-selicrelumab treatment.
Conclusions:
- Neoadjuvant CD40 mAb therapy significantly alters the TME, promoting an anti-tumor immune response.
- These findings provide critical insights for optimizing future clinical trial designs targeting CD40 in cancer treatment.
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