A new immunotherapeutic concept for pancreatic cancer using childhood vaccine recall antigens and Listeria

Background: Pancreatic ductal adenocarcinoma (PDAC) is extremely difficult to cure. Cancer immunotherapy has shown promising results. However, PDAC is poorly immunogenic with few effective neoantigens present, while immune suppression by myeloid-derived-suppressor-cells (MDSC) and tumor-associated-macrophages (TAM) prevents T cell activation in the tumor microenvironment (TME). To address these problems, we developed a novel concept of immunotherapy which includes the generation of memory T cells to a highly immunogenic antigen like tetanus toxoid (TT) before tumor development and reactivation of these memory T cells after tumor development in parallel with delivering TT antigens as an alternative for neoantigens into the tumor cells by an attenuated bacterium Listeria monocytogenes through in vivo infection. When combined with low doses of Gemcitabine (reduces immune suppression by MDSC and TAM) these reactivated TT-specific memory T cells are now able to destroy the Listeria-TT-infected tumor cells. Methods: Before tumor development, memory T cells were generated to a highly immunogenic recall antigen tetanus toxoid (TT) through repeated immunizations with the childhood TT vaccine (like in humans; most individuals have been exposed to during childhood vaccinations). After tumor development, the same mice (Panc-02 or KPC model) received one immunization with a high dose of Listeria-TT to deliver TT inside tumor cells, followed by multiple low doses of Listeria-TT to reactivate the memory T cells to TT. Gemcitabine was administered to reduce immune suppression. CD4, CD8 T cells, MDSC and TAM were analyzed by ELISPOT and/or flow cytometry. Results: Abundant CD4 and CD8 T cell responses producing Interferon-γ, Perforin, Granzyme B, and were observed in the spleens by ELISPOT and flow cytometry. A significant reduction was observed in tumors and metastases of the Panc-02 and KPC mice, with advanced pancreatic cancer. GEM significantly reduced the percentage of MDSC and TAM in blood and/or primary tumors, respectively. Conclusions: Our data demonstrate that delivery of recall antigen Tetanus Toxoid (TT) into tumor cells with help of attenuated Listeria through in vivo infection, in parallel with reactivating existing memory T cells to TT and low doses of GEM, could be a new type of immunotherapy to treat pancreatic cancer. This novel treatment modality of Listeria-TT and GEM warrants further investigation in the clinical setting.