Introduction: Radiofrequency ablation (RFA) is an emerging therapeutic consideration for pancreatic ductal adenocarcinoma (PDAC), as studies show it induces coagulative necrosis and a host adaptive immune response. As we have previously reported, we observe reduced primary tumor size in patients receiving multiple treatments of endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) in combination with chemotherapy. Therefore, we hypothesize that EUS-RFA promotes neoantigen presentation and activation of the adaptive immune system. To address our hypothesis, we evaluated markers of immune activation through analysis of serum from patients receiving multiple treatments of EUS-RFA in combination with standard-of-care chemotherapy.
Methods: We have established a biorepository to analyze systemic markers in patients enrolled in a prospective study. Enrolled patients have been diagnosed with unresectable pancreatic adenocarcinoma and have received up to four treatments of EUS-RFA in combination with FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) or gemcitabine plus nab-paclitaxel (Gemabraxane) standard of care chemotherapy. As we have published increased systemic immune activation and CD4+ and CD8+ T cell activation post-RFA, we analyzed soluble CD40L (sCD40L) levels two months post-treatment when we observed reductions in tumor size monitored during the EUS-RFA procedure.
Results: We analyzed sCD40L [pg/ml], a member of the TNF superfamily expressed on T cells, critical for antigen presentation. We obtained serum samples from pre-treatment and post-treatment. For this study, we selected five patients for examination who received their first EUS-RFA treatment after a range of 9-18 months post-diagnosis. Four patients received FOLFIRINOX, and one received Gemabraxane, cisplatin, 5FU, and liposomal irinotecan. We quantified a significant difference (*P<0.05) in the four patients that received FOLFIRINOX in combination with EUS-RFA with sCD40L values averaging 1,111 pg/ml before EUS-RFA and an average of 1,495 pg/ml 2 months post EUS-RFA. The patient with the most significant response had pre-EUS-RFA sCD40L levels of 82.9 pg/ml and two months post levels of 1597.1 pg/ml. These data indicate that EUS-RFA elevates sCD40L levels.
Discussion: Therapeutic strategies for locally advanced or metastatic PDAC remain limited. CD40L is a protein expressed on the cell surface of activated T cells. Studies have reported differential signaling through interactions with CD40 on antigen-presenting cells, including activation of ERK, PI3K, and NF kB dependent on the cell type activated. Our study shows that EUS-RFA elevates CD40/CD40L signaling. Our results allow us to leverage EUS-RFA-induced effects by implementing this treatment in combination with immunotherapeutic approaches, including CD40 agonist treatment, to improve PDAC patient responses.

CD40L levels after 2 months post EUS-RFA and FOLFIRINOX therapy

CD40L levels after 2 months post EUS-RFA therapy in patient alone who did not receive FOLFIRINOX

Curtis Wray

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