Abstract 1784: IL-7R targeting therapy for immunoregulation and overcoming steroid resistance in cancer and autoimmune disease

Abstract

Abstract The occurrence of autoimmune reactions caused by immune checkpoint blockade in the treatment of cancer indicates the importance of the cross-disciplinary study of malignancy and autoimmune disease. Meanwhile, although steroids have been commonly used for the treatment of malignancies and immune diseases, steroid resistance is a serious prognosis factor and remains an unsolved problem. IL-7R signaling, which physiologically regulates lymphocyte growth and survival, including antigen-responsive T lymphocyte selection, has been implicated in the development of malignancies and autoimmune diseases. However, the biological significance of IL-7R-signaling in steroid treatment is poorly understood. Here, we identified the relationship between unique IL-7R-signaling and steroid-resistance in lymphoid malignancy and demonstrated the presence of steroid-resistant IL-7R-positive lymphocytes in a mouse bone marrow and spleen or in a mouse model of autoimmune arthritis following steroid treatment. We further showed that an anti-IL-7R-antibody conjugated with SN-38 (A7R-ADC-SN-38) has strong anti-tumor effects against both parent and steroid-resistant malignant cells. Although A7R-ADC-SN-38 efficiently eliminated IL-7R-positive cells, IL-7R-negative mature lymphocytes were preserved. Furthermore, inflammation in the mouse autoimmune arthritis model was suppressed to a greater extent by A7R-ADC conjugated to MMAE than by A7R-ADC-SN-38. Strong and specific elimination of enhanced IL-7R-positive cells, a common pathogenesis of both lymphoid malignancy and autoimmune disease, might prevent the development of malignancy or autoimmune disease in high-risk patients. Thus, the use of A7R-ADC may be a promising strategy for the immunoregulation of both malignancy and autoimmune disease and may serve as a new option to steroid therapy. Thus, A7R-ADC may be a promising strategy to treat malignancies and autoimmune diseases and may serve as a novel alternative to steroid therapy. Thus, A7R-ADC may be a promising strategy to treat malignancies and autoimmune diseases and may serve as a novel alternative to steroid therapy. We have evaluated the effectiveness of A7R-ADC in the treatment of other autoimmune or inflammatory diseases involving IL-7R signaling in a preclinical setting for general use. In addition, IL-7R metastatic solid tumors which acquired Il-7R-dependent homing ability of lymphocytes to be spread into many organs may also be promising therapeutic targets of A7R-ADC. We are proceeding the study to advance A7R-ADC for clinical use in both cancer and autoimmune disease Citation Format: Masahiro Yasunaga, Shino Manabe, Yasuhiro Matsumura. IL-7R targeting therapy for immunoregulation and overcoming steroid resistance in cancer and autoimmune disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1784.