Irreversible electroporation of locally advanced pancreatic cancer transiently alleviates immune suppression and creates a window for antitumor T cell activation

Abstract

Purpose: Local tumor ablation through irreversible electroporation (IRE) may offer a novel therapeutic option for locally advanced pancreatic cancer (LAPC). It may also serve as a means of in vivo vaccination. To obtain evidence of the induction of systemic antitumor immunity following local IRE-mediated ablation, we performed an explorative immune monitoring study. Methods: In ten patients enrolled in a clinical trial exploring the safety, feasibility, and efficacy of percutaneous image-guided IRE in LAPC, we determined the frequency and activation state of lymphocytic and myeloid subsets in pre- and post-treatment peripheral blood samples using flow cytometry. Tumor-specific systemic T cell responses to the pancreatic cancer associated antigen Wilms Tumor (WT)1 were determined after in vitro stimulation in an interferon-y enzyme-linked immunospot assay (Elispot), at baseline and at 2 weeks and 3 months after IRE. Results: Our data showed a transient decrease in systemic regulatory T cells (Treg) and a simultaneous transient increase in activated PD-1+ T cells, consistent with the temporary reduction of tumor-related immune suppression after the IRE procedure. Accordingly, we found post-IRE boosting of a pre-existing WT1 specific T cell response in two out of three patients as well as the de novo induction of these responses in another two patients. There was a trend for these WT1 T cell responses to be related to longer overall survival (p = .055). Conclusions: These findings are consistent with a systemic and tumor-specific immune stimulatory effect of IRE and support the combination of percutaneous IRE with therapeutic immune modulation.

Irreversible electroporation plus allogenic Vγ9Vδ2 T cells enhances antitumor effect for locally advanced pancreatic cancer patients

“…Moreover, Zhao et al reported that IRE can potentiate the antitumor efficacy of immunotherapy 5 Scheffer et al demonstrated that IRE of LAPC transiently alleviates immune suppression and creates a window for antitumor T-cell activation. 4,19 In recent years, immune cell therapy has been applied more and more to tumor therapy. 20,21 In TME, T cells are a key component, and treatment with ICIs or adoptive cell infusion has led to breakthroughs in cancer therapy.…”

Analysis of damage-associated molecular pattern molecules due to electroporation of cells in vitro

“…In IRE 18 , 30 , 31 , 32 , 33 , 34 and ECT with either bleomycin or cisplatin 26 , 35 , 36 , 37 used for cancer treatment, involvement and importance of host immune response was demonstrated, counteracting tumor escape mechanisms. 29 , 38 , 39 After these therapies, dying tumor cells can release specific molecules, which are being recognized by the cells of immune system.…”

Irreversible Electroporation for Locally Advanced Pancreatic Cancer

“…52,58,59 One potential advancement in combination therapy integrates immunotherapy with IRE (and chemotherapy), referred to as "electroimmunotherapy". 9 This is based on the latest findings that IRE induces a systemic immune response 4,60,61 following apoptosis and necrosis of tumor cells, resulting in the release of antigens and damage-associated molecular pattern molecules (DAMPs). These DAMPs induce maturation of dendritic cells (DCs) and other antigen presenting cells (APCs) that can subsequently take up the released antigen epitopes, thereby causing systemic activation of the immune system.…”

“…When robust enough, this systemic T cell response could then lead to regression in distant metastases, a process known as the "abscopal effect". 4,62 However, pancreatic cancers are known for their severely immunosuppressive micro-environment, making it difficult for the activated proinflammatory T-cells to participate in tumor destruction. In order to leverage the patients' own activated immune system through the IRE procedure, a combination with immunotherapy in the form of checkpoint inhibitors or other active immune enhancing drugs may be able to create a synergistic effect.…”

“…Minimally invasive ablation techniques present a promising method for the focal destruction of LAPC. [4][5][6][7][8] It comprises both thermal methods, including radiofrequency ablation, microwave ablation and cryo-ablation, and a primarily nonthermal method, known as irreversible electroporation (IRE). The latter technique, in contrast to thermal ablation methods, employs electrical energy in the form of high-voltage electrical pulses that alter the existing cellular transmembrane potential.…”