Abstract 6392: Combination of pulsed electric field, immunotherapy and cisplatin significantly prolongs survival in an orthotopic breast cancer mouse model
Authors: Pastori Chiara , Wagh Mukta , Nafie Ebtesam , Murad Fatima , Trikha Mohit , Neal Robert 
Published: April 2023

Introduction: Pulsed Electric Field (PEF) therapy is a novel approach to treat cancer by providing focal tumor ablation while sparing sensitive structures within the tumor micro-environment. Previous studies have demonstrated that PEF induces immunogenic cell death by activating inflammatory signaling pathways and stimulation of antigen presenting cells withing the tumor micro-environment. PEF ablation provides a tumor focused in situ vaccination strategy that combines with checkpoint blockade. We hypothesized that PEF ablation should synergize with chemotherapy and anti-PD1 in a model where checkpoint inhibitors are inactive.

Experimental Design: To test this hypothesis, we utilized a highly aggressive syngeneic orthotopic triple negative breast cancer 4T1 mouse model that is non-responsive to anti-PD1 and only marginally responsive to cisplatin to determine if this combination treatment could prolong survival. Thirty-two Balb/c mice were inoculated in the mammary fat pad with 200,000 4T1 cells. Once tumors were established (5mm in diameter), animals were randomized to the following groups: (A) Sham/IgG control (n=8; needle inserted but no PEF), (B) PEF only (n=8), (C) cisplatin + anti-PD-1 (n=8) and (D) PEF + cisplatin + anti PD-1 (n=8). Tumors in groups B and D were treated once with PEF. Anti-PD1 and isotype matched control IgG was administered once per week (200μg, i.p injections) starting on the day of PEF (Group D) for four weeks. Cisplatin was administered (2mg/kg, i.v) once per week for four weeks starting on the day of PEF (d=0) for four weeks. All the mammary fat pad tumors were resected when they achieved a tumor volume of ~200 mm3 to recapitulate post-resection metastatic relapse (See Schematic 1).

Results and Conclusions: All mice in the Sham-control IgG group needed to be euthanized by day 43 due to metastases in multiple organs including lungs, bones, liver and brain. All mice in the cisplatin + anti PD-1 group had to be euthanized by day 74. Interestingly, all groups that were treated with PEF survived much longer. On day 90, 28% of mice in the PEF alone group were alive and 43% were alive in the PEF + anti-PD1 + Cisplatin (see Figure 1). The rank-log p-value for the Kaplan-Meier survival curve was statistically significant.

In conclusion, our results demonstrate that PEF treatment in combination with anti-PD1 and Cisplatin significantly prolongs survival in a highly aggressive triple negative breast tumor mouse model that is non-responsive to immunotherapy. These findings support evaluation of PEF in cancer patients that are receiving combination of checkpoint blockade and chemotherapy.

Citation Format: Chiara Pastori, Mukta Wagh, Ebtesam Nafie, Fatima Murad, Mohit Trikha, Robert Neal. Combination of pulsed electric field, immunotherapy and cisplatin significantly prolongs survival in an orthotopic breast cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6392.