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Targeted Silica-Based Bismuth Gadolinium Nanoparticles as Immunotherapy Modulators During Radiation Therapy

N Virani1*, P Rocchi2, O Tillement2, R Berbeco1, (1) Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA, (2) Institute Light and Mater, UMR5306, Lyon1 University-CNRS, Lyon University, Villeurbanne, Frace


(Thursday, 7/16/2020) 11:30 AM - 12:30 PM [Eastern Time (GMT-4)]

Room: Track 3

Purpose: As treatment begins to transition towards incorporation of immunotherapy, some tumors such as triple negative breast cancer (TNBC) still fail to produce improved outcomes largely due to their highly immunosuppressive nature. Therapies to transition TNBC towards a more immunogenic microenvironment open doors for improved patient response. This study focuses on the use of silica-based bismuth gadolinium targeted nanoparticles (ABi-RGD) and radiation therapy for vascular disruption and improved immunostimulatory microenvironment changes in TNBC.

Methods: Mice were inoculated with an immunosuppressive TNBC followed by treatment with vascular targeted ABi-RGD and 10 Gy radiation. Vascular disruption was further coupled with anti-CTLA-4. Primary tumor was resected 14 days post-therapy and stained for immunosuppressive cells (regulatory T-cells and M2 macrophages) and immune activating cells (cytotoxic T-cells, helper T-cells, and M1 macrophages).

Results: In vivo tumor suppression was shown following radiation and ABi-RGD based vascular disruption and anti-CTLA-4 immunotherapy. Vascular disruption significantly delayed primary tumor growth compared to control mice. The addition of anti-CTLA-4 led to improved overall hinderance of secondary metastases and improved primary tumor immune cell infiltration. Vascular disruption increased lymphocyte infiltration, specifically enhancing the cytotoxic to regulatory T-cell ratio indicating a shift in the microenvironment towards a more immunogenic tumor. Vascular disruption therapy also caused an increase in helper T-cells, which are key intermediates for activation of secondary immune cells such as B-cells and macrophages. To study the effects of the improved helper T-cell infiltration, macrophage polarization was evaluated and shown to shift towards anti-tumor M1 cells.

Conclusion: ABi-RGD nanoparticles are an exciting new theranostic development due to their quick clearance, biocompatibility, MRI tracking, and active targeting. With the addition of radiation therapy these particles allow for a multi-pronged treatment of primary tumor and microenvironment priming for immunotherapy of secondary metastases in conventionally immunosuppressive TNBC.


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