Abstract 5026: Efficacy of anti-PD-1, IDO inhibitor, chemotherapy and bone-targeting agent on tumor growth in a syngeneic bone metastasis model of triple-negative breast cancer
Authors: Kähkönen Tiina Emilia , Suominen Mari I. , Mäki-Jouppila Jenni H. , Halleen Jussi M. , Bernoulli Jenni 
Published: September 2020

Abstract
Triple-negative breast cancer (TNBC) is an aggressive cancer with treatment options limited to standard-of-care chemotherapy. TNBC patients develop metastases in high incidence, and almost all patients have bone metastases at end-stage disease. Bone metastases are mainly osteolytic, causing severe bone loss that can be prevented by bone-targeting agents. Currently, there is no efficient cure for bone metastases. Activation of the patient’s own immune system by immunotherapies is widely studied in various cancers, but their efficacy on bone metastases is not well established. In this study, we aimed to evaluate the efficacy of immunotherapies in comparison to standard-of-care compounds in a preclinical TNBC bone metastasis model. Mouse 4T1-GFP TNBC cells were inoculated intracardially to immunocompetent female Balb/c mice to model bone metastasis. Treatment of single agents of chemotherapy (cyclophosphamide, 100 mg/kg), bone-targeting agent (zoledronic acid, 0.1 mg/kg), and immunotherapies programmed cell death 1 antibody (mouse anti-PD-1, 10 mg/kg) and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor (epacadostat, 100 mg/kg), and the combination of anti-PD-1 and epacadostat were started on the day following the cancer cell inoculations. The study was terminated about 2 weeks after the inoculations. Tumor burden was evaluated at sacrifice by GFP imaging in skeleton and soft tissues, and tumor-induced bone loss by X-ray imaging. Tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemical stainings of CD3+, CD4+ and CD8+ T cells. Cyclophosphamide decreased skeletal tumor burden and the area of tumor-induced osteolytic bone lesions. It also decreased the number of soft tissue metastases in ovaries and adrenal glands. Zoledronic acid decreased osteolytic lesion area but had no effect on tumor burden. Anti-PD-1, epacadostat and their combination had no effect on tumor burden, on the development of osteolytic lesions, or on the number of soft tissue metastases. Low number or no TILs were observed in the tumors growing in bone obtained from vehicle-treated mice. Immunotherapies did not prevent tumor growth in bone or tumor-induced bone changes in the syngeneic TNBC model. This is probably a consequence of the low number of TILs in the tumors growing in bone. Further studies are needed to evaluate the effects of treatment combinations and to increase the responsiveness to immunotherapies especially in bone metastases.
Citation Format: Tiina Emilia Kähkönen, Mari I. Suominen, Jenni H. Mäki-Jouppila, Jussi M. Halleen, Jenni Bernoulli. Efficacy of anti-PD-1, IDO inhibitor, chemotherapy and bone-targeting agent on tumor growth in a syngeneic bone metastasis model of triple-negative breast cancer [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 5026.