Pancreas| Volume 168, ISSUE 4, P610-616, October 2020

A phase 1b trial of concurrent immunotherapy and irreversible electroporation in the treatment of locally advanced pancreatic adenocarcinoma



      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.


      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.


      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).


      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.
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        • Konstantinidis I.T.
        • Warshaw A.L.
        • Allen J.N.
        • et al.
        Pancreatic ductal adenocarcinoma: is there a survival difference for R1 resections versus locally advanced unresectable tumors? What is a “true” R0 resection?.
        Ann Surg. 2013; 257: 731-736
        • Skelton R.A.
        • Javed A.
        • Zheng L.
        • He J.
        Overcoming the resistance of pancreatic cancer to immune checkpoint inhibitors.
        J Surg Oncol. 2017; 116: 55-62
        • von Bernstorff W.
        • Voss M.
        • Freichel S.
        • et al.
        Systemic and local immunosuppression in pancreatic cancer patients.
        Clin Cancer Res. 2001; 7: 925s-932s
        • Rahib L.
        • Smith B.D.
        • Aizenberg R.
        • Rosenzweig A.B.
        • Fleshman J.M.
        • Matrisian L.M.
        Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.
        Cancer Res. 2014; 74: 2913-2921
        • Gillen S.
        • Schuster T.
        • Meyer Zum Buschenfelde C.
        • Friess H.
        • Kleeff J.
        Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages.
        PLoS Med. 2010; 7e1000267
        • He J.
        • Ahuja N.
        • Makary M.A.
        • et al.
        2564 resected periampullary adenocarcinomas at a single institution: trends over three decades.
        HPB (Oxford). 2014; 16: 83-90
        • Khan S.
        • Jaggi M.
        • Chauhan S.C.
        Revisiting stroma in pancreatic cancer.
        Oncoscience. 2015; 2: 819-820
        • Khan S.
        • Ebeling M.C.
        • Chauhan N.
        • et al.
        Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer.
        Cancer Res. 2015; 75: 2292-2304
        • Martin 2nd, R.C.
        • Kwon D.
        • Chalikonda S.
        • et al.
        Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy.
        Ann Surg. 2015; 262: 486-494
        • Martin R.C.G.
        An update on the role of irreversible electroporation in locally advanced pancreatic adenocarcinoma.
        HPB (Oxford). 2016; 18: 791-792
        • Martin 2nd, R.C.
        Management of locally advanced pancreatic cancer.
        Surg Clin North Am. 2016; 96: 1371-1389
        • Holland M.M.
        • Bhutiani N.
        • Kruse E.J.
        • et al.
        A prospective, multi-institution assessment of irreversible electroporation for treatment of locally advanced pancreatic adenocarcinoma: initial outcomes from the AHPBA pancreatic registry.
        HPB (Oxford). 2019; 21: 1024-1031
        • Martin 2nd, R.C.
        • Durham A.N.
        • Besselink M.G.
        • et al.
        Irreversible electroporation in locally advanced pancreatic cancer: a call for standardization of energy delivery.
        J Surg Oncol. 2016; 114: 865-871
        • Pandit H.
        • Hong Y.K.
        • Li Y.
        • et al.
        Evaluating the regulatory immunomodulation effect of irreversible electroporation (IRE) in pancreatic adenocarcinoma.
        Ann Surg Oncol. 2019; 26: 800-806
        • Li X.
        • Xu K.
        • Li W.
        • et al.
        Immunologic response to tumor ablation with irreversible electroporation.
        PloS One. 2012; 7e48749
        • Isaji S.
        • Mizuno S.
        • Windsor J.A.
        • et al.
        International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017.
        Pancreatology. 2018; 18: 2-11
        • Evans D.B.
        What makes a pancreatic cancer resectable?.
        Am Soc Clin Oncol Educ Book. 2018; 38: 300-305
        • Martin 2nd., R.C.G.
        Irreversible electroporation of stage 3 locally advanced pancreatic cancer: optimal technique and outcomes.
        J Vis Surg. 2015; 1: 4
        • Martin 2nd, R.C.
        Irreversible electroporation of locally advanced pancreatic neck/body adenocarcinoma.
        J Gastrointest Oncol. 2015; 6: 329-335
        • Wilkowski R.
        • Wolf M.
        • Heinemann V.
        Primary advanced unresectable pancreatic cancer.
        Recent Results Cancer Res. 2008; 177: 79-93
        • Ho C.K.
        • Kleeff J.
        • Friess H.
        • Buchler M.W.
        Complications of pancreatic surgery.
        HPB (Oxford). 2005; 7: 99-108
        • Wainberg Z.A.
        • Hochster H.S.
        • Kim E.J.-H.
        • et al.
        Phase I study of nivolumab (Nivo) + nab-paclitaxel (nab-P) + gemcitabine (Gem) in advanced pancreatic cancer (APC).
        J Clin Oncol. 2019; 37: 298
        • Leen E.
        • Picard J.
        • Stebbing J.
        • Abel M.
        • Dhillon T.
        • Wasan H.
        Percutaneous irreversible electroporation with systemic treatment for locally advanced pancreatic adenocarcinoma.
        J Gastrointest Oncol. 2018; 9: 275-281
        • Lawrence M.S.
        • Stojanov P.
        • Polak P.
        • et al.
        Mutational heterogeneity in cancer and the search for new cancer-associated genes.
        Nature. 2013; 499: 214-218
        • Shitara K.
        • Nishikawa H.
        Regulatory T cells: a potential target in cancer immunotherapy.
        Ann N Y Acad Sci. 2018; 1417: 104-115
        • Sallusto F.
        • Geginat J.
        • Lanzavecchia A.
        Central memory and effector memory T cell subsets: function, generation, and maintenance.
        Annu Rev Immunol. 2004; 22: 745-763
        • Yamaguchi K.
        • Mishima K.
        • Ohmura H.
        • et al.
        Activation of central/effector memory T cells and T-helper 1 polarization in malignant melanoma patients treated with anti-programmed death-1 antibody.
        Cancer Sci. 2018; 109: 3032-3042
        • Manjarrez-Orduno N.
        • Menard L.C.
        • et al.
        Circulating T cell subpopulations correlate with immune responses at the tumor site and clinical response to PD1 inhibition in non-small cell lung cancer.
        Front Immunol. 2018; 9: 1613