Introduction: Pancreatic ductal adenocarcinoma (pancreatic cancer), is the 4th leading cause of cancer deaths. This “silent killer” is characterized by its development of metastases often before the primary tumor can be detected, resulting in a five-year survival rate of only 4%. Gemcitabine and erlotinib, FDA-approved drugs for pancreatic cancer, improve median survival by less than six months in advanced stage patients, underscoring the need for additional and/or new alternative approaches. Cancer immunotherapy could be such new approach because of its great promise for metastatic cancer, however hurdles need to be overcome. The first hurdle is that tumor-associated antigens (TAA) used in most cancer vaccines are poorly immunogenic, and the second hurdle is immune suppression, particularly by myeloid-derived suppressor cells (MDSC) that prevent T cell activation in the tumor microenvironment (TME). To address these problems we have developed a novel strategy using an attenuated bacterium Listeria monocytogenes that delivers highly immunogenic antigens selectively into tumor cells of metastases and tumors combined with Gemcitabine (GEM) to reduce immune suppression through MDSC. We have cloned highly immunogenic recall antigens (RA) such as tetanus toxoid (TT), poliovirus (PV), and measlevirus (MV) antigens into the Listeria to activate existing memory T cells to foreign highly immunogenic antigens, which most individuals have been exposed to during childhood through vaccinations, and to deliver these antigens selectively into tumor cells. Memory T cells generated to the RA following childhood vaccinations circulate in their blood for life and can upon reactivation kill the infected tumor cells with high efficiency. We have previously demonstrated this with Listeria-TT in a triple-negative breast cancer model 4T1. Listeria and GEM also kill tumor cells through reactive oxygen species (ROS). In the current study we analyzed whether GEM could improve the efficacy of Listeria-TT immunotherapy in mice with pancreatic cancer (Panc-02 model). Experimental procedures: Tumor-bearing mice (pre-immunized with the human TT vaccine) were treated with GEM and Listeria-TT, and effects were analyzed on metastases, tumors, and MDCS. Results: We found that Listeria-TT combined with GEM resulted in a near complete elimination of metastatic pancreatic cancer (metastases and tumors), which was not possible with Listeria-TT or GEM alone. We also found that GEM reduced the MDSC population by 50% in the blood. Currently, we are analyzing CD8 T cell responses of treated and control mice with pancreatic cancer to immunodominant epitopes within the TT protein (TT1162-1169:SNWYFNHL and TT12-86-1294:LNIYYRRL) matching the H2-b haplotype. In conclusion, the combination of GEM and Listeria-TT eliminated metastatic pancreatic cancer in the Panc-02 model. We expect that this dramatic effect is a combination of immune-based and non-immune-based mechanisms. Future prospects: Since the cloned recall antigen fragments also contain many T cell epitopes recognized in humans, we expect that these constructs are directly translatable to human clinical trials in the near future. Finally, cancer patients could be tested in advance by revaccination with human childhood vaccines to determine to which antigens they react to best before starting the Listeria-recall antigen vaccine therapy. Based on patient's best response (most likely determined by MHC haplotype and the TME), a personalized therapy with the best combination of recall antigen(s) could be designed.
Citation Format: Dinesh Chandra, Wilber Quispe-Tintaya, Arthee Jahangir, Alice Kwon, Rodrigo Alves da Silva, Lukman Solola, Ziqiang Yuan, Steven K. Libutti, Claudia Gravekamp. Novel use of Listeria and gemcitabine to improve immunotherapy for pancreatic cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B076.
- ©2016 American Association for Cancer Research.