To avoid dose-limiting adverse events associated with CAF reprogramming, Panagi, Mpekris, and Chen et al. loaded tranilast into micelles for delivery. Due to enhanced intratumoral accumulation and CAF uptake of the micelles, low, frequent doses of tranilast induced superior reprogramming and stroma normalization compared to a 100-fold higher dose of free drug. Combining tranilast micelles with epirubicin micelles, Doxil, and/or immunotherapy further increased T cell infiltration, resulting in cures and protection in models otherwise resistant to immunotherapy. Reduced tumor stiffness/desmoplasia, as measured by shear wave elastography, predicted responses.
Contributed by Lauren Hitchings
ABSTRACT: Nano-immunotherapy improves breast cancer outcomes but not all patients respond and none are cured. To improve efficacy, research focuses on drugs that reprogram cancer-associated fibroblasts (CAFs) to improve therapeutic delivery and immunostimulation. These drugs, however, have a narrow therapeutic window and cause adverse effects. Developing strategies that increase CAF-reprogramming while limiting adverse effects is urgent. Here, taking advantage of the CAF-reprogramming capabilities of tranilast, we developed tranilast-loaded micelles. Strikingly, a 100-fold reduced dose of tranilast-micelles induces superior reprogramming compared to free drug owing to enhanced intratumoral accumulation and cancer-associated fibroblast uptake. Combination of tranilast-micelles and epirubicin-micelles or Doxil with immunotherapy increases T-cell infiltration, resulting in cures and immunological memory in mice bearing immunotherapy-resistant breast cancer. Furthermore, shear wave elastography (SWE) is able to monitor reduced tumor stiffness caused by tranilast-micelles and predict response to nano-immunotherapy. Micellar encapsulation is a promising strategy for TME-reprogramming and SWE is a potential biomarker of response.
Author Info: (1) Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. (2) Cancer Biophysics Laboratory, Department of Mec
Author Info: (1) Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. (2) Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. (3) Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Bunkyo, Tokyo, Japan. (4) Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. (5) Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Bunkyo, Tokyo, Japan. (6) Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Bunkyo, Tokyo, Japan. (7) Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan. Department of Integrated Biosciences, Laboratory of Cancer Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwanoha, Kashiwa, Chiba, Japan. (8) Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan. (9) The Center for the Study of Hematological and other Malignancies, Nicosia, Cyprus. (10) The Center for the Study of Hematological and other Malignancies, Nicosia, Cyprus. (11) Center for Stem Cell Research (a unit of inStem Bengaluru), Christian Medical College Campus Bagayam, Vellore, Tamil Nadu, India. (12) Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. Basic and Translational Cancer Research Center, School of Sciences, European University of Cyprus, Nicosia, Cyprus. (13) Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. (14) Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Bunkyo, Tokyo, Japan. (15) Basic and Translational Cancer Research Center, School of Sciences, European University of Cyprus, Nicosia, Cyprus. (16) Basic and Translational Cancer Research Center, School of Sciences, European University of Cyprus, Nicosia, Cyprus. (17) Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. (18) The Center for the Study of Hematological and other Malignancies, Nicosia, Cyprus. Karaiskakio Foundation, Nicosia, Cyprus. (19) The Center for the Study of Hematological and other Malignancies, Nicosia, Cyprus. Karaiskakio Foundation, Nicosia, Cyprus. Cyprus Cancer Research Institute, Nicosia, Cyprus. (20) Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, Japan. (21) Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan. (22) Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan. Institute for Future Initiatives, The University of Tokyo, Bunkyo, Tokyo, Japan. (23) Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Bunkyo, Tokyo, Japan. horacio@bmw.t.u-tokyo.ac.jp. (24) Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus. tstylian@ucy.ac.cy.
