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Checkpoint Blockade Inhibitors in Combination with Radiation Therapy in Breast Cancer

B Sanstrum, R Piranlioglu, F Kong, C Ferguson, J Barret, H Korkaya, A Al-Basheer*, Augusta University, Augusta, GA

Presentations

(Sunday, 7/12/2020)   [Eastern Time (GMT-4)]

Room: AAPM ePoster Library

Purpose: Utilize radiation therapy to increase the efficacy of checkpoint blockade inhibitors of the stress-induced heat shock protein 70 (HSP70) in order to reverse immunosuppression and induce neo-antigens to improve the outcomes of patients with the triple-negative breast cancer (TNBC) subtype

Methods: This study utilized 6-week old female BALB/c 4T1 tumor-bearing mice as a model for TNBC. Combination treatment of HSP70 inhibitors and targeted irradiation was performed prior to tumor resection and data collection. Radiation Therapy doses were planned and delivered using a Small Animal Radiation Platform (SARRP) equipped with on-board cone-beam CT. A single fraction of 17 Gy (Two fractions of 11.5 Gy) doses were delivered based on EQD2 calculation (alpha Beta ratio = 4). To achieve highly localized dose delivery, an x-ray collimator was used to focus the broad beam from a 225 kVp x-ray tube.

Results: Our preliminary data provide evidence that targeting HSP70 in combination with radiation therapy has dual activity on the tumor and the immunosuppressive microenvironment. HSP70 blockade significantly reduces the immunosuppressive MDSC infiltration in lungs by more than 50% compared to lungs from control mice. This also led to increased tumor infiltration of effector T cells from 1-2% in controls to 12% in lungs from mice treated with HSP70 inhibitor in combination with radiation. Interestingly, T cell infiltration is further increased to 20% when checkpoint blockade inhibitor is combined with HSP70 inhibitor and radiation.

Conclusion: In summary, our studies elucidate the molecular mechanism by which HSP70 cytoprotects tumor cells from cytotoxic agents while regulating the immunosuppressive MDSCs which limits the anti-tumor activity of TILs. They also provide evidence that blocking HSP70 potentiates the efficacy of the check point blockade particularly when combined with radiation in syngeneic mouse models representing TNBC subtype.

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