Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

Summary

Even with current promising antitumor antibodies, their antitumor effects on stroma-rich solid cancers have been insufficient. We employed mild hyperthermia intending to improve drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce: MIAPaCa-2; moderate: BxPC-3; and abundant: Capan-1 and Ope-xeno). Cetuximab (1 mg/kg) was administered systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures: 25°C (control), 37°C (intra-abdominal organ level), or 41°C (mild hyperthermia) (n = 4 each). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa-2 model; moderate (1063) in the BxPC-3 model; and negative in the Capan-1 and Ope-xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8-fold (2980, 3015) in the BxPC-3 model, 2.5- or 4.8-fold (1881, 3615) in the Capan-1 model and 3.2- or 4.2-fold (1469, 1922) in the Ope-xeno model, respectively. Cetuximab was effective in treating even stroma-rich and k-ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.

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