Abstract B132: A new concept of cancer immunotherapy by targeting pancreatic ductal adenocarcinoma through a childhood recall antigen

Abstract

Patients with pancreatic ductal adenocarcinoma (PDAC) have a five-year survival of only 6%. Cancer immunotherapy has shown promising results for metastatic cancer but only in 20% of the patients. Our lab has developed a new concept of immunotherapy using an attenuated non-pathogenic bacterium Listeria monocytogenes for the selective delivery of a highly immunogenic recall antigen tetanus toxoid (TT) into tumor cells of pancreatic tumors and metastases. Most individuals have been exposed to TT during childhood vaccinations and memory T-cells to TT circulate in blood for live. These memory T-cells to TT can be reactivated by Listeria-TT at any time in life and will now destroy the infected tumor cells. Low doses of gemcitabine (GEM) were added to further improve T-cell responses. Panc-02 and KPC mice were immunized with the “human TT vaccine” to generate memory T-cells before development of the pancreatic cancer. After cancer development, mice were treated with Listeria-TT and GEM, and tumors (weight) and metastases (number) were analyzed by eye in the Panc-02 mice, and by SUVmax (measurement of tumor growth) in the KPC mice. T-cell responses in the spleen were analyzed by flow cytometry and ELISPOT, and KPC tumors were analyzed by RNAseq. Listeria-TT and GEM nearly completely eliminated both early and advanced pancreatic cancer in Panc-02 and KPC mice, in correlation with abundant CD4 and CD8 T-cell responses producing perforin, granzyme B, or IFNγ, in vivo or in vitro, respectively. RNAseq analysis of “treated” KPC tumors showed a strong influx of CD4 and CD8 T-cells, upregulation of multiple granzymes, perforin, co-stimulatory molecules, and cell death pathways. These results suggest the multiple synergistic effects of Listeria-TT and GEM on pancreatic cancer. This novel treatment modality of Listeria-TT and GEM warrants further investigation in a clinical setting. Citation Format: Benson C. Selvanesan, Dinesh Chandra, Wilber Quispe, Ankur Patel, Kiran Meena, Steven K. Libutti, Ziqiang Yuan, Jennifer Chuy, Claudia Gravekamp. A new concept of cancer immunotherapy by targeting pancreatic ductal adenocarcinoma through a childhood recall antigen [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B132.