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Abstract 4203: Tumor-targeted delivery of a neoantigen surrogate by non-pathogenic Listeria reduces metastatic ovarian cancer


 Objectives: End-stage ovarian cancer is commonly characterized by intraperitoneal (IP) carcinomatosis and chemoresistance. To date, immune-mediated therapies have shown little success in this population in part due to the absence of neoantigens in these tumors and strong immune suppression in the tumor microenvironment (TME) preventing T cell activation. Our laboratory has developed a novel microbial-based immunotherapeutic strategy for selective delivery of a highly immunogenic tetanus toxoid protein (TT856-1313) into tumor cells through in vivo infection with attenuated Listeria monocytogenes. In mice previously vaccinated against TT, this leads to reactivation of pre-existing TT-specific memory T cells which kill the infected tumor cells in mouse models of pancreatic cancer. The addition of gemcitabine (GEM) improves T cell responses by reducing immune suppression in the TME. We hypothesize that the regimen Listeria-TT+GEM will have efficacy in vivo in mice with advanced ovarian cancer.
 Methods: Infection and killing of mouse and human ovarian tumor cells by Listeria-TT was analyzed in vitro. C57Bl/6 mice were vaccinated with the TT vaccine at six weeks of age. 3x106 luciferase-expressing ID8 syngeneic mouse tumor cells (Id8-Luc) were injected IP and tumor growth was monitored by Vivo Imaging Systems (IVIS.) Mice were divided into four treatment groups: saline, GEM, Listeria-TT, and Listeria-TT+GEM. Quantification of tumor burden was approximated by total flux (photons/second) within a region of interest (ROI) prior to, during, and at completion of therapy (days 0, 9, and 19 after tumor cell injection, respectively).
 Results: In vitro analyses demonstrated efficient infection and killing of mouse Id8-Luc and chemoresistant human Hey ovarian tumor cells by Listeria-TT. The response of tumors and metastases to the four prespecified treatment regimens was evaluated by IVIS as described above. On Day 0, there was no significant difference in the quantified tumor burden between the four treatment groups. On Days 9 and 19, the tumor burden was significantly less in the Listeria-TT+GEM group compared to the saline group (Mann-Whitney p=0.0159). Neither GEM nor Listeria-TT alone were significantly different from the saline group on day 9, but the effect of GEM was significantly different from saline on day 19 (p=0.0079). In a follow up study, the survival time of the Listeria-TT+GEM-treated mice was improved by 50% compared to the saline mice. The survival of GEM compared to saline is under investigation.
 Conclusions: Our results demonstrate that Listeria-TT+GEM strongly reduced metastatic ovarian cancer in mice. Additional experiments are ongoing to evaluate if more treatment cycles of Listeria-TT+GEM further improves the survival time. This study suggest that the combination therapy may be promising for human application.
 Citation Format: Lisa R. Gabor, Olivia R. Khouri, Ken Lin, Nicole Nevadunsky, Dennis Yi-Shin Kuo, Claudia Gravekamp. Tumor-targeted delivery of a neoantigen surrogate by non-pathogenic Listeria reduces metastatic ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4203.