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. 2025 Apr;32(4):2786-2798.
doi: 10.1245/s10434-024-16742-3. Epub 2024 Dec 29.

Enhancing the Immunotherapeutic Effect by IP-001 and Irreversible Electroporation in Mouse Oligometastatic Models of Pancreatic Adenocarcinoma

Yan Li  1 , Samuel S K Lam  2 , Yonglin Gao  3 , Emily Shore  3 , David W Anderson  2 , Tomas Hode  2 , Robert C Martin  4
Affiliations

Enhancing the Immunotherapeutic Effect by IP-001 and Irreversible Electroporation in Mouse Oligometastatic Models of Pancreatic Adenocarcinoma

Yan Li et al. Ann Surg Oncol. 2025 Apr.

Abstract

Background: This study aimed to evaluate the immunotherapeutic effect of irreversible electroporation (IRE) and IP-001 in pancreatic adenocarcinoma with metastasis.

Methods: Orthotopic models of pancreatic adenocarcinoma with hepatic oligometastasis were established by implantation of tumor tissues (derived from Pan02 or KPC cells) size 2 mm3 into the pancreas and left liver lobe in C57BL/6J mice. One week after implantation, the tumor-burden mice were subjected to saline control, IRE, IP-001, and IRE+IP-001. For IRE therapy (1000 V, 0.1 ms, 10 pulses administered 10 times), the pancreas tumor was treated, whereas the oligometastasis was untreated as the IRE off-target tumor. Intratumoral administration of IP-001(0.4 ml/kg) was performed.

Results: In the KPC oligometastatic model, IRE+IP-001 therapy significantly suppressed the growth of oligometastatic tumor. Flow cytometry showed significantly increased tumor-infiltrating lymphocytes (TILs) (e.g., CD8+ cytotoxic T lymphocytes) and significantly increased monocytes/macrophages in the oligometastatic tumor tissues from IRE+IP-001 treatment compared with the sham control. Significantly decreased Treg cells and tumor-associated macrophages (TAMs) also were found in the oligometastatic tumor tissues from IRE+IP-001 treatment compared with the sham control. In the Pan02 oligometastatic model, both IRE+IP-001 therapy and IRE+anti-PD-L1 immunotherapy significantly suppressed the growth of oligometastatic tumor, which was associated with the increased CD8+ cytotoxic T lymphocytes. However, increased monocytes/macrophages were found in the mice that had IRE+IP-001 therapy, but not in the mice that had IRE+anti-PD-L1 immunotherapy.

Conclusion: The study provided compelling evidence for the efficacy of IRE&IP-001 therapy in suppressing pancreatic tumors, including off-target oligometastatic lesions. The observed off-target effect underscores the importance of systemic immune activation in achieving effective tumor control.

Keywords: IP-001; Immune-modulation; Irreversible electroporation; N‐dihydrogalactochitosan; Pancreatic adenocarcinoma.

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Conflict of interest statement

Disclosure: Immunophotonics provided the IP-001 as an unrestricted educational grant. Robert C. Martin is a paid educational consultant for Angiodynamics, a manufacturer of IRE. Samuel S. K. Lam is a full-time employee of Immunophotonics, Inc and one of the authors listed in one of the IPs of IP-001. David Anderson is an employee of Immunophotonics and a shareholder. The remaining authors have no conflicts of interest.

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