Abstract 6381: Superior effects of polymeric micelles in reprogramming tumor microenvironment and enhancing nano-immunotherapy
Authors: Panagi Myrofora , Mpekris Fotios , Chen Pengwen , Voutouri Chrysovalantis , Nakagawa Yasuhiro , Martin John D. , Hiroi Tetsuro , Hashimoto Hiroko , Ishii Genichiro , Kojima Motohiro , Kataoka Kazunori , Cabral Horacio , Stylianopoulos Triantafyllos 
Published: June 2022

Abstract
Nano-immunotherapy has high potential to improve cancer patient outcomes, as already demonstrated in triple negative breast cancer with the combination of nanoparticle albumin-bound paclitaxel and the immune checkpoint blocker antibody, atezolizumab. This regimen, however, does not lead to complete cure with median survival lasting less than two years. To increase patient survival, research focuses on repurposing common drugs to modulate the tumor microenvironment (TME), aiming to increase delivery of nanoparticles, antibodies and other drug regimens and improve immunostimulation. These drugs, however, exhibit certain dose-limitations and are associated with adverse effects. Here, taking advantage of the TME reprogramming capabilities of the approved antihistamine drug tranilast, we developed polymeric tranilast-loaded nanoparticles and explored their potential to modulate the TME more efficiently than the free drug. The results were striking as the micellar formulation of tranilast administered in a dose 100 times lower than that of the free drug reported superior reprogramming effects in two syngeneic triple negative breast tumor models. These effects were due to the enhanced intratumoral accumulation and cancer-associated fibroblast uptake of the nanoparticles compared to the free drug. Tranilast micelles were also found to promote significantly the delivery and efficacy of epirubicin micelles, overcome immune checkpoint resistance and induce tumor immunogenicity. Overall, the proposed micelles improved the efficacy of nano-immunotherapy in both breast cancer tumor models leading to complete cure. Furthermore, we employed the non-invasive and clinically applied ultrasound shear wave elastography method to monitor changes in tumor stiffness, which is the first effect caused by the tranilast micelles, and thus to determine an optimal dose-scheduling. Importantly, we found that tumor stiffness before the initiation of nano-immunotherapy was able to predict the efficacy of the treatment providing strong evidence for the potential of shear wave elastography to be used as a biomarker predictive of response. Our findings are very encouraging indicating that a) encapsulation of TME modulating drugs improves their pharmacokinetic properties, while allows for drastic reduction in the dose of administration, b) modulation of the TME can lead to complete cures of nano-immunotherapy in resistant to this therapy breast cancer tumor models, and c) ultrasound shear wave elastography can be employed for optimizing the use of TME modulating agents and for the prediction of tumor response to nano-immunotherapy allowing for optimized treatment protocols.
Citation Format: Myrofora Panagi, Fotios Mpekris, Pengwen Chen, Chrysovalantis Voutouri, Yasuhiro Nakagawa, John D. Martin, Tetsuro Hiroi, Hiroko Hashimoto, Genichiro Ishii, Motohiro Kojima, Kazunori Kataoka, Horacio Cabral, Triantafyllos Stylianopoulos. Superior effects of polymeric micelles in reprogramming tumor microenvironment and enhancing nano-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6381.