425P - Engineered <italic>Lactococcus lactis</italic> as a personalized cancer vaccine platform induces antitumour immunity via membrane-inserted peptide for neoantigens

Background

Personalized neoantigen peptide-based therapeutic cancer vaccines, designed to trigger de novo T cell responses against neoantigens, are always considered safe and highly specific to tumours of individual patients, which can amplify and broaden the endogenous repertoire of tumour-specific T cells. However, naked peptide vaccines are often faced with significant challenges such as early enzymatic degradation, poor antigen presentation by dendritic cells (DCs), tumour low immunogenicity, and limited lymph nodes (LNs) trafficking. Therefore, an effective tumour vaccine vector which can rapidly display peptides and promote antigen cross-presentation is urgently needed. Compared with other biomaterials such as Montanide ISA-51 and injectable hydrogels, probiotics which participate in human health dynamically and closely can be utilized as a promising delivery system with the integration of synthetic biology and chemical biotechnology.

Methods

We developed a probiotic food-grade Lactococcus lactis-based in situ vaccination (FOLactis) expressing a fusion protein of Fms-like tyrosine kinase 3 ligand and co-stimulator OX40 ligand, physically attaching neoantigen peptides onto the FOLactis cell wall (Ag-FOLactis) by using a cell penetrating peptide sequence derived from human immunodeficiency virus Tat N-terminally. The in vivo metabolism and biodistribution of Ag-FOLactis was explored using near infrared living imaging. We also checked the neoantigen-reactive T cell response in vivo and ex vivo by flow cytometry.

Results

Ag-FOLactis can keep in the injection site, slow the degradation of peptides and attract DCs to present antigens. In multiple tumour-bearing mouse models, locoregional administration of Ag-FOLactis in lymph nodes significantly triggers tumour-specific T cell response, inhibits tumour growth and prolongs the survival of tumour-bearing mice. Ag-FOLactis also synergizes with an anti-PD1 antibody.

Conclusions

Overall, we find that Ag-FOLactis represents a flexible and powerful personalized cancer vaccine platform for displaying different neoantigen peptides, with enhanced specific anti-tumour immunity and little harm to important organs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.