Combined chemoradiotherapy and PARP inhibition in pancreatic cancer to induce a synchronous inflammatory cytokine response.

Abstract

29 Background: Outcomes remain poor for patients with locally advanced pancreas cancer despite advances in combined modality therapy. Radiation and chemotherapy remain the mainstay of treatment for unresectable locally advanced pancreas cancer, and the addition of various agents is currently being assessed in clinical trials. There is increasing evidence that local inflammation and host immune response play a role in anti-tumor activity. We aimed to assess the impact of combined chemoradiotherapy and PARP inhibition on inflammatory cytokine production in pancreas cancer patients. Methods: A clinical trial of concurrent use of a PARP inhibitor with chemoradiation was performed on a cohort of 34 patients. Serum samples were collected at baseline and weekly during intensity modulated radiotherapy treatment. Concentrations of various inflammatory cytokines were measured in picograms per milliliter using a chemiluminescent assay. Comparisons between average percentage change from baseline to peak change of serum cytokine concentration across all patients was performed using a paired T test. Results: Multiple inflammatory cytokines experienced a statistically significant increase after patient treatment. Peak serum increase occurred within 3-5 weeks after treatment initiation for the majority of cytokines tested. The most significantly increased pro-angiogenic cytokines included placental growth factor (p = 2.21x10-6) and vascular endothelial growth factor (p = 1.19x10-4), which peaked at weeks 4 and 5, respectively. Multiple members of the interleukin family also increased significantly. Both IL-7 (p = 1.89x10-4) and IL-17a (p = 7.26x10-4) peaked at weeks 4. IL-5 (p = 8.84x10-5) and IL-15 (p = 1.26x10-15) peaked at weeks 3 and 4, respectively. Conclusions: Patients receiving combined PARP inhibitor and chemoradiation experience a stereotyped increase in inflammatory cytokine signaling that peaks at approximately 1 month after initiation of treatment. Changes in serum inflammatory cytokines may serve as biomarkers of response to treatment and could underpin future combined treatment modalities including immunomodulating agents.