Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

BACKGROUND: Cytotoxic 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 FINDINGS: EGFRminicellsDox 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/SIGNIFICANCE: Targeted 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

Combined Tumor Cell-Based Vaccination and Interleukin-12 Gene Therapy Polarizes the Tumor Microenvironment in Mice

Tumor progression depends on tumor milieu, which influences neovasculature formation and immunosuppression. Combining immunotherapy with antiangiogenic/antivascular therapy might be an effective therapeutic approach. The aim of our study was to elaborate an anticancer therapeutic strategy based on the induction of immune response which leads to polarization of tumor milieu. To achieve this, we developed a tumor cell-based vaccine. CAMEL peptide was used as a B16-F10 cell death-inducing agent. The lysates were used as a vaccine to immunize mice bearing B16-F10 melanoma tumors. To further improve the therapeutic effect of the vaccine, we combined it with interleukin (IL)-12 gene therapy. IL-12, a cytokine with antiangiogenic properties, activates nonspecific and specific immune responses. We observed that combined therapy is significantly more effective (as compared with monotherapies) in inhibiting tumor growth. Furthermore, the tested combination polarizes the tumor microenvironment, which results in a switch from a proangiogenic/immunosuppressive to an antiangiogenic/immunostimulatory one. The switch manifests itself as a decreased number of tumor blood vessels, increased levels of tumor-infiltrating CD4+, CD8+ and NK cells, as well as lower level of suppressor lymphocytes (Treg). Our results suggest that polarizing tumor milieu by such combined therapy does inhibit tumor growth and seems to be a promising therapeutic strategy

Identification of Building Wall Orientation Angle with Multilook Synthetic Aperture Radars Processing

A new technique of identifying orientation angles of walls of buildings has been proposed in this paper. The present method is based on multilook processing. The aim of this work is to find the relationships between the received signals reflected from uniform targets (e.g. walls, parts of buildings, etc.) positioned at different orientation angles towards the radar platform. The technique is dedicated for synthetic aperture radars systems. It can be used to extend target identification in synthetic aperture radars images obtained by a single-channel antenna. In this paper, theoretical analysis is presented and verified with simulated radar data

Takayasu’s arteritis: a rare disease in Poland

Introduction. Takayasu’s arteritis (TA) is a rare and potentially life-threatening granulomatous large-vessel vasculitis that involves mostly in the aorta and its proximal branches, and occurs most commonly in young females. This study measures the incidence and prevalence of TA, and assesses the gender distribution and territorial differences in the occurrences of this disease in Poland over a five-year period. To the best of our knowledge, this is the first evaluation of this rare disease in Poland based on a hospital morbidity database. Materials and method. Analyses were performed with population-based administrative data obtained from a national hospital morbidity study carried out between January 2011 – December 2015 by the Polish National Institute of Public Health. Yearly incidence rates and prevalence of TA were calculated using the number of TA patients and corresponding census data for the overall Polish population. Results. Data included 660 hospitalization records. The final study sample comprised 177 patients: 154 female (87%) and 23 male (13%) with first-time hospitalization for TA. The mean age was 45.4years (95% CI: 42.9–47.8; SD 16.8; range 4–81 years), median 47. The incidence rate of TA was estimated at 0.92 per million per year (95% CI: 0.68–1.16). Five-year TA prevalence was estimated to be 4,6 per million. Incidence rates of TA did not vary significantly between more urban and more rural regions. Conclusions. The incidence of TA in Poland was similar or lower to data reported by other European countries. The study provides epidemiological data on TA in Poland that may be useful while comparing it with other geographical regions