Title : The immunogenicity and anti-tumor efficacy of a rationally designed neoantigen vaccine for B16F10 mouse melanoma

Abstract:

Tumor neoantigens are ideal targets for cancer immunotherapy as they are recognized by host immune system as foreigners and can elicit tumor-specific immune responses. However, existing strategies utilizing RNA or long peptides for the neoantigen vaccines render limited immune responses since only 20%-30% of neoantigens predicted in silico to bind MHC I molecules are capable of eliciting immune responses with the majority of responding T cells are CD4⁺. Therefore, it warrants further exploration to enhance neoantigen-specific CD8⁺ T cells responses. Since neoantigens are naturally weak antigens, we asked whether foreign T help epitopes could enhance their immunogenicity. In present study, we chose four weak B16F10 neoantigens as vaccine targets, and fused them to the transmembrane domain of diphtheria toxin, namely DTT-neoAg. Strikingly, the vaccine elicited anti-tumor CD8⁺ T cells responses and enhanced tumor infiltration of both T cells and NK cells. Impressively, DTT-neoAg vaccine significantly deterred tumor growth with the inhibition rate reached 88% in the preventive model and 100% in therapeutic model at low dose of tumor challenge. Furthermore, after second challenge with higher dose of tumor cells, 33.3% of the immunized mice remain tumor-free for 6 months in the therapeutic model. Because DTT is a nontoxic domain of diphtheria toxin, it may be not of great concern in terms of safety as a Th epitope provider. Thus the fusion strategy employed by this study may become a feasible and powerful approach for development of personalized cancer vaccine.

Presentation Learning Outcome

• Our DTT-neoAg vacccine significantly expand the pool of effective vaccine targets, which should benefit cancer patients with intermediate/low mutation burdens such as Ovary cancer, Prostate cancer, low grade Glioma, Chronic lymphocytic leukemia, and Acute myeloid leukemia.
   
• The strategy of using DTT to enhance the immune response of weak immunogenic neoantigen could be applied to any weakly immunogenic antigen.
   
• In our novel neoantigen vaccine design, neoantigen targets selection only needs to consider that mutations are non-synonymous and that the corresponding proteins are highly expressed. Immunogenicity prediction and immune response verification can be skipped. This will simplify the neoantigen screening process.
   
• Since DTT is a non-toxic domain of the toxin molecule, its safety would not be of great concern as a vaccine adjuvant. It will be more feasible for development of personalized cancer vaccines in clinical trials.