Targeting immunoliposomes to EGFR-positive glioblastoma

Abstract

Background:We assessed the capacity of epidermal growth factor receptor (EGFR)-targeted immunoliposomes to deliver cargo to brain tumor tissue in patients with relapsed glioblastoma harboring an EGFR amplification. We aimed to assess the tolerability and effectiveness of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in glioblastoma multiforme patients. Patients and methods: Patients with EGFR-amplified, relapsed glioblastoma were included in this phase I pharmacokinetic trial. Patients received up to four cycles of anti-EGFR ILs-dox. Twenty-four hours later, plasma and cerebrospinal fluid (CSF) samples were obtained. In addition, we also treated three patients with anti-EGFR ILs-dox before resection of their relapsed glioblastoma. Doxorubicin concentrations were measured in plasma, CSF, and tumor tissue. Safety and efficacy parameters were also obtained. Results: There were no or negligible levels of doxorubicin found in the CSF demonstrating that anti-EGFR ILs-dox are not able to cross the bloodebrain barrier (BBB). However, significant levels were detected in glioblastoma tissue 24 h after the application, indicating that the disruption of BBB integrity present in high-grade gliomas might enable liposome delivery into tumor tissue. No new safety issues were observed. The median progression-free survival was 1.5 months and the median overall survival was 8 months. One patient undergoing surgery had a very long remission suggesting that neoadjuvant administration may have a positive effect on outcome. Conclusions: We clearly demonstrate that anti-EGFR-immunoliposomes can be targeted to EGFR-amplified glioblastoma and cargodin this case doxorubicindcan be delivered, although these immunoliposomes do not cross the intact BBB. (The GBM-LIPO trial was registered as NCT03603379).

Optimal Physicochemical Properties of Antibody–Nanoparticle Conjugates for Improved Tumor Targeting

“…[118] However, the therapeutic effi cacy results in breast cancer remain dismal. [119,120] Depending on the results of the ongoing phaseII clinical trials, [121] the cost of production (antibodies production, NPs synthesis, con jugation, and batch reproducibility) [122,123] versus therapeutic improvement will need further analysis to justify such conju gation strategy.…”

Exploring Responses of Glioblastoma Patient-Derived Cell Cultures to Drugs Reveals New Therapeutic Opportunities

“…Low dose of DOX was safe for patients, even with extended (>6 weeks) dosing [146]. Promising results were also observed in phase I trial (GBM-LIPO trial) in which patients with relapsed glioblastoma harboring an EGFR amplification were treated with anti-EGFR doxorubicin-loaded immunoliposomes (anti-EGFR ILsdox) [63].…”

“…The anti-EGFR-doxorubicin-loaded immunoliposomes (ILs-DOX) displayed highly efficient binding and internalization in a panel of EGFR and EGFRvIII overexpressing cells [61,62]. Recently, a small trial with anti-EGFR ILs-DOX on relapsed GBMs with EGFR amplification showed positive response in one patient [63].…”

Lipid Nanoparticles Functionalized with Antibodies for Anticancer Drug Therapy

“…After a phase 1 dose-escalation trial (NCT01702129) in advanced solid tumors, C225-ILs-Dox was clinically evaluated in patients with relapsed or refractory high-grade gliomas (NCT03603379). Although the delivery of C225-ILs-dox to glioblastoma tissue was demonstrated, no other definitive conclusions can be drawn from this trial, as there was no control group, and only a few patients were treated [ 115 ]. The DOX-loaded PEGylated immunoliposome termed MCC-465 utilizes the F(ab’) 2 fragment of human GAH mAb as the targeting ligand, which positively reacts to over 90% of gastric cancer tissues but negatively to all normal tissues.…”