Enabling tumour immune cell infiltration through application of a novel surgical device

Declan M Soden, PhD, Michael O’Riordan, MD, FRCSI, FRCSI, Patrick Forde, PhD, Michael Bourke, MD, FRCSI. Mercy University Hospital.

Background: ‘Electroporation’ is a term used to describe the permeabilization of the cell membrane following the application of short and intense electric fields across the cell membrane. When it is used in combination with chemotherapeutic drugs the effect is to focus the local absorption of drug into the electro-permeabilised cells.  Our group has pursued the development of this unique non-thermal technology to allow for the electro-permeabilisation of gastrointestinal tumour tissue in order to enable the perfusion and absorption of low dose chemotherapy agents directly into the tumour. While electroporation induces local tumour ablation the release of ATP from electroporated cells and tumour associated antigens (structurally intact after the non-thermal electroporation induced cell death) results in an active lymphocyte tumour cell infiltration post treatment which we have demonstrated to have a synergistic combination with anti-CTLA4 and PD1 antibodies. NK, and CD8+ T cell levels compared to controls increase by over 5 fold within a 48-72 hour window post electroporation treatment.

 

Objective: To enable progression free survival through enabling an activated tumour antigen CD8+ T cell response.

 

Design: Colorectal tumour models (murine and canine) were employed to evaluate efficacy in addition porcine models were used to assess safety.

 

Interventions: The endoscopic device was connected to an electroporation generator and manoeuvred into position with the tumour where vacuum and electroporation pulses were then delivered. Chemotherapeutic agents were delivered either intravenously or via direct intratumoural injection.

Main outcome measurements: Changes in tumour volume were measured and histology reports of treated tissue obtained.

 

Results: Electroporation is effective at facilitating the tumour-targeted absorption of chemotherapy by gastrointestinal cancers, significantly reducing the drug concentrations required for tumour control to be achieved. Healthy tissue remained largely unaffected by the procedure. A large tumour infiltration of dendritic, natural killer and macrophagic cells post procedure was also recorded along with the presence of CD8+ T cells. When combined with either PD1 or anti-CTLA4 antibodies a systemic immune response was generated in murine models (CT26) with curative responses obtained i.e. no tumour growth on rechallenge.

Conclusions: No adverse events were noted in this study with the study demonstrating the clear potential clinical benefits from enabling an interventional endoscopic approach to debulk gastrointestinal cancers. The synergistic combination with new immunotherapy approaches indicates the potential for this treatment as a neoadjuvant therapy for gastrointestinal cancers.