Abstract PO-081: LR-IL-22 protects the intestine to facilitate whole abdomen irradiation in ovarian cancer
Authors: Hamade Diala Fatima , Fisher Renee , Hou Wen , Shields Donna , Epperly Michael W. , Greenberger Joel S. 
Published: April 2021

Abstract
Ovarian cancer is the most lethal gynecological cancer worldwide with an estimated 152,000 deaths per year. Despite optimal management with radical cytoreductive surgery and subsequent platinum/taxane-based chemotherapy, most patients, will suffer recurrence within 18 months. Our laboratory has recently discovered a new therapeutic agent for intestinal radiation protection, namely the novel second-generation probiotic Lactobacillus reuteri (LR) genetically engineered to produce the radioprotective cytokine Interleukin-22 (IL-22) (Zhang et al. In Vivo, 34(1):39-50, 2020 Jan-Feb). To demonstrate that LR-IL-22 could protect the intestines from irradiation, we used three mouse models (total body irradiation (TBI), whole abdomen irradiation (WAI) and partial body irradiation (PBI)). For TBI, C57BL/6 mice were irradiated to 9.25 Gy to the entire body. For WAI, C57BL/6 mice were irradiated using a linear accelerator so that only the abdomen was irradiated to 19.75 Gy with the remainder of the body shielded from the irradiation. PBI was performed with the right rear leg shielded with the rest of the body irradiated to 15 Gy. In all three models the mice were gavaged 24 hours after irradiation with 1 × 109 LR-IL-22 cells. The mice were followed for development of either the hematopoietic syndrome (TBI) or gastrointestinal syndrome (WAI or PBI). In separate experiments we determined if mice irradiated as above had decreased irradiation induced inflammation using a Luminex assay on the intestine and blood plasma from mice sacrificed on days 0, 1, 2, 3, 5 and 7 following irradiation. We also determined whether intraoral gavage of LR-IL-22 24 hours prior to irradiation might protect the tumor in a mouse ovarian tumor model. Murine ovarian tumor cells 2F8-cis were injected intraperitoneally into Muc1 transgenic mice. Seventy-two hours later the mice were irradiated to 16 Gy WAI and followed for tumor growth. In the TBI model, mice treated with LR-IL-22 24 hours prior to irradiation had an increased survival of 80% compared to 0% in control irradiated mice (p = 0.0001). In the WAI model, mice treated with LR-IL-22 had a 40% survival following 19.75 Gy compared to 0% in the control irradiated group (p = 0. 0100). Following the PBI dose of 15 Gy, mice treated with LR-IL-22 had a 70% survival compared to 0% for the control irradiation only mice (p = 0.0006). Decreased expression of several inflammatory proteins such as TNF-α, IL-6 and IFN-γ (p = 0.0423, 0.0473 and 0.0024, respectively) was also detected in mice treated with LR-IL-22 24 hours prior to WAI compared to control irradiated mice. Furthermore, two weeks after injecting Muc1 transgenic mice with tumors, the nonirradiated mice had more than 200 small tumor nodules disseminated throughout the peritoneum while control WAI mice or mice treated with intraoral LR-IL-22 prior to WAI had no more than 10 tumor nodules. Hence, intraoral LR-IL-22 prior to chemoradiation may protect the intestines and result in increased survival of ovarian cancer patients.
Citation Format: Diala Fatima Hamade, Renee Fisher, Wen Hou, Donna Shields, Michael W. Epperly, Joel S. Greenberger. LR-IL-22 protects the intestine to facilitate whole abdomen irradiation in ovarian cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-081.