Abstract P4-06-02: Chemoimmunotherapy with cyclophosphamide plus a toll-like receptor 9 (TLR9) agonist eradicates triple negative breast cancer in a murine model

Abstract

Abstract Background. Toll-like receptors (TLR) recognize conserved molecular patterns expressed by microbes and together with other molecular sensors serve as a first line of defense, inducing soluble and cellular mediators of innate immunity and initiating key steps of an adaptive immune response. The use of TLR agonists for therapeutic purposes relies on the ability of these compounds to induce, at least partially, some of the immune events that occur during natural infections. For example, synthetic CpG-containing oligodeoxynucleotides (ODN) act as TLR9 agonists, mimicking stimulation of the immune system by bacterial or viral DNA. CpG ODNs are being developed for cancer immunotherapy based on their capacity to stimulate innate and adaptive anti-tumor responses. In this study, we examined the efficacy of intratumorally administered CpG-ODN 1826 alone or in combination with immunomodulatory antibodies (anti-PD-1, anti-OX40, anti-CTLA4) or chemotherapy (cyclophosphamide, paclitaxel) in the syngeneic mouse 4T1 breast tumor model. Methods. Tumors were implanted orthotopically in the mammary fat pads on the left and right flanks while only one tumor was injected with CpG-ODN 1826. Therapy began 12-14 days post tumor injection when tumors were 8-10 mm in diameter. CpG-ODN 1826 (100 ug) was administered intratumorally, while immunomodulatory antibodies (anti-PD-1 [200 ug], anti-CTLA4 [100 ug], anti-OX40 [400 ug]) and chemotherapies (cyclophosphamide [150 mg/kg], paclitaxel [10 mg/kg]) were administered intraperitoneally. Tumor volume was monitored on both flanks to assess direct and abscopal/systemic anti-tumor activity. Tumor tissue obtained during the treatment regimen was used to evaluate therapy-induced changes in the immune microenvironment. Results. CpG-ODN 1826, administered intratumorally over 5 consecutive days induced complete regressions in ˜50% of the treated tumors, but only delayed growth in the distant lesions. The immunomodulatory antibodies had little effect on their own and did not add to the therapeutic efficacy of CpG-ODN 1826. The best therapeutic efficacy was obtained with a combination of weekly cyclophosphamide + CpG-ODN 1826 resulting in complete regression of both the CpG injected tumors and the contralateral tumors in 100% of the mice. Conclusions. These data support the clinical investigation of the combination of a TLR9 agonist (CpG-ODN) with cyclophosphamide in women with breast cancer. Citation Format: Campbell MJ, Tandon V, Senman B, Li J, Esserman L. Chemoimmunotherapy with cyclophosphamide plus a toll-like receptor 9 (TLR9) agonist eradicates triple negative breast cancer in a murine model [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-02.