Abstract
BackgroundCytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers.Methodology/Principle FindingsEGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs).Conclusions/SignificanceTargeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma.
Highlights
Brain cancer treatment remains a major challenge in oncology
Leaky vasculature is typical of tumors, resulting in an enhanced permeation-retention effect (EPR), which promotes enhanced accumulation of nanoparticles in tumor tissue compared to normal tissues [5]
Overall 2 dogs had a complete response (CR) to therapy, 2 had a partial response (PR) to therapy (90% - 98.95% reduction in tumor volume), 10 had stable disease (SD), and 1 showed progressive disease (PD)
Summary
Brain cancer treatment remains a major challenge in oncology. Leaky vasculature is typical of tumors, resulting in an enhanced permeation-retention effect (EPR), which promotes enhanced accumulation of nanoparticles in tumor tissue compared to normal tissues [5]. The EPR effect is weaker than that observed in peripheral tumors [4], which reduces extravasation of small particles from the leaky vasculature [5, 6] and limits therapeutic efficacy of systemic chemotherapy and targeted therapies in brain tumors [7,8,9]. This study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers
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