Abstract 6244: Turning poorly vascularized tumors into highly vascularized tumors with nanoparticles: Proof of concept and pharmacometric analysis

Abstract

Abstract Combinatorial regimen are a mainstay in oncology. Taxanes and trastuzumab are both gold standards for HER2 positive breast cancer. To what extent they could reshape tumor micro-environment remains to be elucidated. The aim of this study was to compare in breast cancer mice models the antiproliferative efficacy and impact on tumor neo-angiogenesis of trastuzumab stealth immunoliposomes encapsulating docetaxel and stealth liposomal docetaxel associated with free trastuzumab. Nude mice bearing human MDA-MB-231 breast cancer tumors were treated by saline (control), docetaxel liposome (5mg/kg) associated with free trastuzumab (1.9 mg/kg) or trastuzumab immunoliposome (eq. 5 mg/kg docetaxel and 1.9 mg/kg trastuzumab) QW for 4 consecutive weeks. Tumor growth was monitored twice a week by volumetric measurement using a caliper. Blodd vessels density was evaluated in vivo by fluorescence imaging using Angiosense as a vascular probe plus ex-vivo using anti-CD31 antibodies and electronic microscopy at 2, 4 and 6 weeks. A specific algorithm was developed on MatLab for imaging analysis. No treatment-induced toxicities was observed. After 4 weeks of dosing, no difference in efficacy was seen between treatments (p=0.798) and Angiosense imaging did not show differences either (p=0.628). However electronic microscopy showed that both immunoliposomes and liposomes increased tumor vascular density as compared with control. In addition, a difference between treatments was evidenced because a marked increase in vascularization of central tumors VS. peripheral tumors was observed with trastuzumab immunoliposome as compared with standard docetaxel liposome (p=0.00023). A numerical model based on porous medium theory combined with multi-scale approaches has been derived to describe the spatial distribution of the drugs within tissues. Overall our data suggest that trastuzumab stealth immunoliposomes induce a normalization of tumor vessels with an increase in blood vessels density in central tumors. This could pave the way for sequencing combinatorial strategies so as to improve drug delivery into tumors of the associated treatments. Citation Format: Guillaume Sicard, Anne Rodallec, Florian Correard, Cristina Vaghi, Clair Poignard, Joseph Ciccolini, Sébastien Benzekry, Arnauld Sergé, Raphaelle Fanciullino. Turning poorly vascularized tumors into highly vascularized tumors with nanoparticles: Proof of concept and pharmacometric analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6244.