BACKGROUND: Combining immune checkpoint blockade therapy with operative disruptive immunomodulation using irreversible electroporation may overcome the resistance to systemic therapy found in patients with locally advanced, unresectable pancreatic cancer. We describe the safety profile and efficacy of IRE with nivolumab. METHODS: In the preclinical phase of study, human pancreatic cell lines were cultured with interferon-γ (10 ng/mL) and murine models of pancreatic cancer were treated with irreversible electroporation and programmed death ligand-1 (PD-L1) expression was measured. In this phase 1b clinical trial (NCT03080974), surgical ablative irreversible electroporation was performed followed by nivolumab. The primary end point was dose-limiting toxicity. RESULTS: Human pancreatic cells express PD-L1 when cultured with interferon-γ: quantitative polymerase chain reaction MiaPaca (15.2 rel. fold ± 0.5; P < .01) and S20-13 (31.0 rel. fold ± 4.4; P < .01). Murine orthotopic tumors treated by irreversible electroporation had an increase in signal intensity score for the expression of PD-L1 in residual tumor (P < .01). Ten patients were included in the safety analysis with a 12-month median follow-up (interquartile range 6.0, 15.8). No dose-limiting toxicities occurred. Seven patients developed grade 3/4 treatment-related adverse events; none required a dose modification of nivolumab; nivolumab-related adverse events occurred in 1 patient. Mean time to progression was 6.3 months (confidence interval 3.5-10.0) with current median overall survival of 18.0 months (confidence interval 9.2-26.8). CONCLUSION: Irreversible electroporation induces expression of PD-L1 in vitro. Combination therapy with concurrent nivolumab is well tolerated. A multicenter, phase 2 adjuvant trial is underway using irreversible electroporation and nivolumab in patients with locally advanced pancreatic cancer.
BACKGROUND: Combining immune checkpoint blockade therapy with operative disruptive immunomodulation using irreversible electroporation may overcome the resistance to systemic therapy found in patients with locally advanced, unresectable pancreatic cancer. We describe the safety profile and efficacy of IRE with nivolumab. METHODS: In the preclinical phase of study, human pancreatic cell lines were cultured with interferon-γ (10 ng/mL) and murine models of pancreatic cancer were treated with irreversible electroporation and programmed death ligand-1 (PD-L1) expression was measured. In this phase 1b clinical trial (NCT03080974), surgical ablative irreversible electroporation was performed followed by nivolumab. The primary end point was dose-limiting toxicity. RESULTS:Human pancreatic cells express PD-L1 when cultured with interferon-γ: quantitative polymerase chain reaction MiaPaca (15.2 rel. fold ± 0.5; P < .01) and S20-13 (31.0 rel. fold ± 4.4; P < .01). Murine orthotopic tumors treated by irreversible electroporation had an increase in signal intensity score for the expression of PD-L1 in residual tumor (P < .01). Ten patients were included in the safety analysis with a 12-month median follow-up (interquartile range 6.0, 15.8). No dose-limiting toxicities occurred. Seven patients developed grade 3/4 treatment-related adverse events; none required a dose modification of nivolumab; nivolumab-related adverse events occurred in 1 patient. Mean time to progression was 6.3 months (confidence interval 3.5-10.0) with current median overall survival of 18.0 months (confidence interval 9.2-26.8). CONCLUSION: Irreversible electroporation induces expression of PD-L1 in vitro. Combination therapy with concurrent nivolumab is well tolerated. A multicenter, phase 2 adjuvant trial is underway using irreversible electroporation and nivolumab in patients with locally advanced pancreatic cancer.
Authors: Khan Mohammad Imran; Margaret A Nagai-Singer; Rebecca M Brock; Nastaran Alinezhadbalalami; Rafael V Davalos; Irving Coy Allen Journal: Front Oncol Date: 2022-03-18 Impact factor: 5.738
Authors: Xiaoju Shi; Conor O'Neill; Xingtong Wang; Yujia Chen; Youxi Yu; Min Tan; Guoyue Lv; Yan Li; Robert C Martin Journal: Am J Cancer Res Date: 2021-06-15 Impact factor: 6.166
Authors: Brandon J Burbach; Stephen D O'Flanagan; Qi Shao; Katharine M Young; Joseph R Slaughter; Meagan R Rollins; Tami Jo L Street; Victoria E Granger; Lalit K Beura; Samira M Azarin; Satish Ramadhyani; Bruce R Forsyth; John C Bischof; Yoji Shimizu Journal: Nat Commun Date: 2021-06-23 Impact factor: 17.694