Multiparametric MRI to Predict Response to Irreversible Electroporation Plus Anti-PD-1 Immunotherapy in Pancreatic Ductal Adenocarcinoma.

[PURPOSE] To investigate contrast-enhanced T1-weighted MRI and diffusion-weighted magnetic resonance imaging (DWI) for early prediction of tumor response to combined irreversible electroporation (IRE) and anti-PD-1 immunotherapy.

[METHODS] Murine pancreatic ductal adenocarcinoma (PDAC) cells KRAS* were inoculated into the pancreas of C57BL/6 mice. IRE was performed when tumors became palpable. After IRE, mice received six intraperitoneal injections of anti-PD-1 over 2 weeks. T2-weighted MRI, T1-weighted MRI with macromolecular contrast agent poly(L-glutamic acid)-conjugated gadolinium (PG-Gd), and DWI were performed before and after IRE. Survival was analyzed using Kaplan-Meier curves. Mice surviving at least 100 days without recurrence after IRE were considered complete responders. Relationships between MRI findings and treatment response were assessed with one-way ANOVA, Student's t-test, and receiver operating characteristic (ROC) analysis.

[RESULTS] Tumor volume on T2-weighted MRI at early treatment time-points did not correlate with survival. T1-weighted MRI with PG-Gd clearly showed increased PG-Gd uptake in tumors on days 4 and 11-14 after IRE and anti-PD-1 immunotherapy. Higher PG-Gd uptake correlated with longer survival (R = 0.634; p < 0.0001). Area-under-the-ROC curve had high predictive value for treatment outcome (0.805; p = 0.033). Immunofluorescence staining confirmed high accumulation of macrophages in tumors after treatment. On DWI, all KRAS* tumors exhibited significantly increased apparent diffusion coefficient (ADC) values 7, 11, and 14 days after combination therapy. Moreover, pretreatment tumor ADC values were significantly higher in complete responders than in partial responders (p = 0.0025).

[CONCLUSION] PG-Gd contrast-enhanced T1-weighted MRI and DWI are potential predictors of response to combined IRE and anti-PD-1 immunotherapy in PDAC.