Abstract
Doxorubicin-loaded anti-EGFR immunoliposomes had antitumor activity in a phase I trial.
Major finding: Doxorubicin-loaded anti-EGFR immunoliposomes had antitumor activity in a phase I trial.
Approach: Pegylated liposomes containing doxorubicin were linked to antigen-binding fragments of cetuximab.
Impact: Targeted delivery of cytotoxic compounds to tumors with immunoliposomes may be feasible.
Immunoliposomes, nanoparticles in which a liposome drug carrier is covalently linked to an antibody, can potentially maximize drug efficacy and minimize toxicity by directly delivering thousands of drug molecules to antigen-expressing tumors. Mamot and colleagues conducted a first-in-man open-label phase I dose-escalation trial of doxorubicin-loaded anti-EGFR immunoliposomes (anti-EGFR ILs-dox) in which pegylated liposomal doxorubicin was covalently linked to antigen-binding fragments of cetuximab. The primary endpoint of the trial was to establish the maximum tolerated dose. Heavily pretreated patients with advanced EGFR-overexpressing solid tumors were enrolled, and the maximum tolerated dose was reached at 50 mg/m2, although safety was assessed only until 30 days after the last dose. Additionally, 1 suicide and 1 case of acute psychosis in patients with preexisting psychiatric disorders were not counted as dose-limiting toxicities, nor was a fatal bleed in a patient with head and neck cancer caused by tumor necrosis and carotid artery erosion. Interestingly, the spectrum of other adverse events was different than those caused by EGFR inhibitors or free doxorubicin, which may be due to a different mechanism of action. Among the 26 patients evaluated for the primary endpoint, 1 patient had a complete response, 1 had a partial response, and 10 had stable disease, suggesting that anti-EGFR ILs-dox had antitumor activity, although biodistribution analyses were not performed to show preferential accumulation in tumor tissue. The tumors of the patients with objective responses did have high EGFR expression, but the study size was too small to determine whether response was correlated with EGFR expression. Although additional evaluation of safety and efficacy is needed, these trial results provide evidence that it may be feasible to use immunoliposomes to selectively deliver cytotoxic drugs to tumors.
