Abstract Background The intracellular bacterium Listeria monocytogenes is an attractive vector for cancer immunotherapy as it can effectively deliver tumor antigens to antigen-presenting cells, leading to a robust antitumor response.Results In this study, we developed a novel vaccine platform called Listeria-based Live Attenuated Double Substitution (LADS), which involves introducing two amino acid substitutions (N478AV479A) into the virulence factor listeriolysin O (LLO).LADS is a safe vaccine platform, with an attenuation of nearly 7000-fold, while 143 retaining complete immunogenicity due to the absence of deletion of any virulence factors.
We developed two LADS-based vaccines, LADS-E7 and LADS-AH1, which deliver the human papillomavirus (HPV) type 16 E7 oncoprotein and murine colon carcinoma immunodominant antigen AH1, respectively.Treatment with LADS-E7 Western Saddle Synthetic or LADS-AH1 significantly inhibited and regressed established tumors, while also dramatically increasing the populations of tumor-infiltrated antigen-specific CD8+ T cells.RNA-sequencing analysis of tumor tissue samples revealed that LADS-E7 altered the expression of genes related to the immune response.
Moreover, intratumoral injection of LADS-based vaccines induced strong antitumor responses, generating systemic antitumor responses to control distant tumor growth.Encouragingly, LADS-E7 or LADS-AH1 immunization effectively prevented tumor formation and growth.Conclusions Our findings demonstrate that LADS-based vaccines represent a more powerful platform for the development of immunotherapeutic and preventive vaccines against cancers and infectious diseases.