Presentation 「Intraperitoneal radioimmunotherapy (ipRIT) with 64Cu-PCTA-cetuximab to treat peritoneal dissemination of colon cancer in a mice model of peritoneal seeding」

吉井, 幸恵  ,  yoshimoto, Mitsuyoshi  ,  Matsumoto, Hiroki  ,  Ming-Rong, Zhang  ,  Sugyo, Aya  ,  Tsuji, Atsushi  ,  Higashi, Tatsuya

Objectives: Peritoneal dissemination is a frequent cause of death from gastrointestinal cancers. Conventional therapy such as surgery and chemotherapy provide limited benefits to patients with peritoneal dissemination. To develop a new therapeutic strategy, we applied an intraperitoneal radioimmunotherapy (ipRIT) with 64Cu-PCTA-anti-EGFR antibody (cetuximab) to a mouse model of peritoneal seeding with human colon cancer HCT116 cells. Methods: HCT116 cells stably expressing red fluorescent protein (HCT116-RFP) were ip seeded at 1 week before 64Cu-PCTA-cetuximab administration. At first, we compared biodistribution in tumors and normal organs between ip and intravenous (iv) injection of 64Cu-PCTA-cetuximab. Tumors in the peritoneum were isolated under a fluorescent stereoscopic microscope and densitometric analysis was performed to measure radioactivity in the tumors. Organs of interest were collected, radioactivity and weight were measured to calculate %ID/g, and dosimetry analysis was performed. For in vivo therapy study, mice were ip injected with 64Cu-PCTA-cetuximab (22.2 MBq). For comparison, administration of saline and 64Cu-PCTA-trastuzumab (22.2 MBq), cetuximab and trastuzumab without 64Cu (5 mg/kg, twice a week for 80 days), were examined. Trastuzumab was selected as a negative antibody because of its low binding affinity to HCT 116 cells. Tumor growth was monitored using in vivo fluorescent imaging, and survival was observed in each mouse. Results: The biodistribution study revealed that accumulation in tumors ip injected with 64Cu-PCTA-cetuximab showed higher than that iv injected. In the ip-injected group, the radioactivity in ascites fluid was high at the early time points (1 – 6 h), thereafter rapid clearance from the peritoneal cavity was observed. Dosimetry analysis demonstrated that the estimated absorbed doses to ip-injected pancreas and large intestine were relatively high (0.0456 mSv/MBq and 0.0384 – 0.0377 mSv/MBq, respectively). However, the human radiation doses to these organs, which were estimated using the administration dose based on body weight, were sufficiently low compared to the reported tolerance doses. In vivo therapy study showed that 64Cu-PCTA-cetuximab inhibited tumor growth and extended survival significantly (P < 0.05) compared to the other treatment groups, which showed little tumor growth inhibition and no significant difference in survival versus saline control. There were no significant body weight loss and changes in hematological and hepatorenal parameters in all the treatment groups in this study. Conclusions: The ipRIT with 64Cu-PCTA-cetuximab effectively inhibited tumor growth and elongated survival with little toxicity in a peritoneal seeding model using HCT116-RFP cells. The therapy could be a promising option to treat the patients with peritoneal dissemination from gastrointestinal cancers.Research support: This work was mainly supported by Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED) and Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED.

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