Efficacy of Bivalent CEACAM6/4-1BBL Genetic Vaccine Combined with Anti-PD1 Antibody in HCT116 Xenograft Mice

Abstract Background:Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Anti-PD1/PD-L1 drugs are feasible treatment for CRC, and genetic vaccine is a promising immunotherapy for cancers. However, anti-tumor efficacy of genetic vaccines including CEACAM6/4-1BBL genes combined with immunocheckpoint inhibitors on CRC has not been reported. We used human colon cancer cell line (HCT116) to establish a xenograft mouse model, and applied [89Zr]-labeled PD-L1 antibody ([89Zr]KN035) for PET imaging. Methods:Attenuated Salmonella typhimurium 3261 was transformed by eukaryotic expression plasmid containing CEACAM6/4-1BBL genes as an anti-tumor vaccine, and the combined anti-tumor immunotherapy with bivalent genetic vaccine and anti-PD1 antibody was conducted. MicroPET was performed to non-invasively and dynamically observe the changes of tumor tissues and expression of PD-L1. Results:We found that the recombinant double-gene plasmids were stably expressed in COS7 cells. The findings showed PD-L1 expression in HCT116 tumor model, and thus anti-PD1/PD-L1 drug was suitable for the treatment and [89Zr]KN035 could be used in whole-body PET imaging for in vivo observation of the model. Efficacy observation results of tumor growth, PET scanning and immunohistochemical assays showed that the combined therapy had obvious improvement in effectiveness over vaccine alone.Conclusions:This study supports that combination of genetic vaccines and anti-immunocheckpoint immunotherapy can inhibit HCT116 tumor growth and provide better efficacy via overcoming the immune tolerance and suppressive microenvironment and inhibiting the immune brake induced by immunocheckpoint activation.