Li Yan, Lam Samuel S K, Gao Yonglin, Shore Emily, Anderson David W, Hode Tomas, Martin Robert C
Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA.
Immunophotonics Inc, St. Louis, MO, USA.
Ann Surg Oncol. 2025 Apr;32(4):2786-2798. doi: 10.1245/s10434-024-16742-3. Epub 2024 Dec 29.
This study aimed to evaluate the immunotherapeutic effect of irreversible electroporation (IRE) and IP-001 in pancreatic adenocarcinoma with metastasis.
Orthotopic models of pancreatic adenocarcinoma with hepatic oligometastasis were established by implantation of tumor tissues (derived from Pan02 or KPC cells) size 2 mm 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.
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.
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.
本研究旨在评估不可逆电穿孔（IRE）和IP - 001对转移性胰腺腺癌的免疫治疗效果。
通过将大小为2毫米的肿瘤组织（源自Pan02或KPC细胞）植入C57BL / 6J小鼠的胰腺和左肝叶，建立伴有肝寡转移的胰腺腺癌原位模型。植入一周后，对荷瘤小鼠进行生理盐水对照、IRE、IP - 001以及IRE + IP - 001处理。对于IRE治疗（1000V，0.1ms，10个脉冲，重复10次），对胰腺肿瘤进行处理，而寡转移灶作为IRE的非靶向肿瘤未进行处理。进行瘤内注射IP - 001（0.4ml / kg）。
在KPC寡转移模型中，IRE + IP - 001治疗显著抑制了寡转移肿瘤的生长。流式细胞术显示，与假手术对照相比，IRE + IP - 001处理的寡转移肿瘤组织中肿瘤浸润淋巴细胞（TILs）（如CD8细胞毒性T淋巴细胞）显著增加，单核细胞/巨噬细胞也显著增加。与假手术对照相比，IRE + IP - 001处理的寡转移肿瘤组织中调节性T细胞和肿瘤相关巨噬细胞（TAM）也显著减少。在Pan02寡转移模型中，IRE + IP - 001治疗和IRE +抗PD - L1免疫治疗均显著抑制了寡转移肿瘤的生长，这与CD8细胞毒性T淋巴细胞增加有关。然而，接受IRE + IP - 001治疗的小鼠中单核细胞/巨噬细胞增加，而接受IRE +抗PD - L1免疫治疗的小鼠中未出现这种情况。
该研究为IRE&IP - 001治疗在抑制胰腺肿瘤（包括非靶向寡转移病灶）方面的疗效提供了有力证据。观察到的非靶向效应强调了全身免疫激活在实现有效肿瘤控制中的重要性。
