⁶⁴Cu-Intraperitoneal Radioimmunotherapy: A Novel Approach for Adjuvant Treatment in a Clinically Relevant Preclinical Model of Pancreatic Cancer

Abstract

Pancreatic cancer (PC) has a very poor prognosis. Surgery is the primary treatment for patients with resectable PC; however, local recurrence, hepatic metastasis, and peritoneal dissemination often occur even after extensive surgery. Adjuvant chemotherapy, typically with gemcitabine, has been used clinically but with only a modest survival benefit. To achieve a better outcome, we investigated the efficacy of 64 Cu-intraperitoneal radioimmunotherapy (ipRIT) with 64 Cu-labeled antiepidermal growth factor receptor antibody cetuximab as an adjuvant treatment after PC surgery using an orthotopic xenografted mouse model. Methods:The efficacy of adjuvant 64 Cu-ipRIT was investigated in a human PC mouse model harboring orthotopic xenografts of xPA-1-DC cells. To reproduce the clinical situation, PC xenografts were surgically resected when pancreatic tumors were readily visible but not metastatic tumors. Increasing doses of 64 Cu-cetuximab were intraperitoneally injected, and the mice were monitored for toxicity to determine the safe therapeutic dose. For adjuvant 64 Cu-ipRIT, the day after tumor resection, the mice were intraperitoneally administered 22.2 MBq of 64 Cu-PCTA-cetuximab and the survival was compared with that in surgery-only controls. For comparison, adjuvant chemotherapy with gemcitabine was also examined using the same model. Results: The mouse model not only developed primary tumors in the pancreas but also subsequently reproduced local recurrence, hepatic metastasis, and peritoneal dissemination after surgery, which is similar to the manifestations that occur with human PC. Adjuvant 64 Cu-ipRIT with 64 Cu-labeled cetuximab after surgery effectively suppressed local recurrence, hepatic metastasis, and peritoneal dissemination in this model. Significant improvement of the survival with minimal toxicity was achieved by adjuvant 64 Cu-ipRIT compared with that in control mice that underwent surgery only. Adjuvant chemotherapy with gemcitabine nominally prolonged the survival, but the effect was not statistically significant. Conclusion: 64 Cu-ipRIT with cetuximab can be an effective adjuvant therapy after PC surgery.

Immuno-OpenPET: a novel approach for early diagnosis and image-guided surgery for small resectable pancreatic cancer

“…Although we observed a clear survival benefit from the immuno-OpenPET-guided surgery, 80% of the treated mice ultimately experienced local recurrence and peritoneal metastasis in this model. To avoid these recurrences, adjuvant chemotherapy or adjuvant therapy with intraperitoneal-administered 64 Cu-PCTA-cetuximab 19 should be considered as additional options.…”

“…cell culture and small resectable orthotopic xenograft model. Human PC xPA-1 cells expressing red fluorescent protein in the cytoplasm and green fluorescent protein in the nucleus (xPA-1-dual color, xPA-1-DC) (AntiCancer) with EGFR overexpression 19 were used for establishment of the mouse model. xPA-1-DC cells were cultured in RPMI-1640 medium (Wako) supplemented with 10% fetal bovine serum in a humidified atmosphere of 95% air and 5% CO 2 at 37 °C.…”

“…Tumors were weighed and radioactivity levels were measured with a γ-counter (1480 Wizard 3; PerkinElmer). The percentage of injected dose per gram (%ID/g) was evaluated as reported previously 19 .…”

“…We previously demonstrated that OpenPET with intraperitoneal administration of anti-epidermal growth factor receptor (EGFR) antibody cetuximab labeled with 64 Cu (β + decay 0.653 MeV, 17.4%; β − decay, 0.574 MeV, 40%; electron capture, 42.6%) was useful for the diagnosis and guided surgery of gastrointestinal cancer-derived tumors in the mouse peritoneal cavity, and intraperitoneal administration of this probe led to their higher accumulation than intravenous injection 18 . Subsequently 19 , we demonstrated the potential of intraperitoneal administration of 64 Cu-cetuximab as an adjuvant treatment for PC, since EGFR (the target of cetuximab) is overexpressed in up to 90% of PCs 20,21 , and the β − particles and high-linear energy transfer Auger electrons from 64 Cu can effectively damage tumor cells. Indeed, intraperitoneal-administrated 64 Cu-cetuximab was efficiently delivered to PC within the pancreas as well as to liver metastases and peritoneal dissemination, and was effective as an adjuvant treatment after PC surgery in a clinically relevant orthotopic PC xenografted mouse model 19 .…”

“…Subsequently 19 , we demonstrated the potential of intraperitoneal administration of 64 Cu-cetuximab as an adjuvant treatment for PC, since EGFR (the target of cetuximab) is overexpressed in up to 90% of PCs 20,21 , and the β − particles and high-linear energy transfer Auger electrons from 64 Cu can effectively damage tumor cells. Indeed, intraperitoneal-administrated 64 Cu-cetuximab was efficiently delivered to PC within the pancreas as well as to liver metastases and peritoneal dissemination, and was effective as an adjuvant treatment after PC surgery in a clinically relevant orthotopic PC xenografted mouse model 19 .…”