LAUSR

Neoantigen vaccine is a promising breakthrough in tumor immunotherapy. However, the application of this highly personalized strategy in the treatment of solid tumors is hindered by several obstacles, including very costly and time-consuming preparation steps, uncertainty in prediction algorithms and tumor heterogeneity. Universalization of neoantigen vaccine is an ideal yet currently unattainable solution to such limitations. To overcome these limitations, we engineered oncolytic viruses co-expressing neoantigens and neoantigen-binding major histocompatibility complex (MHC) molecules to force ectopic delivery of peptide-MHC ligands to T cell receptors (TCRs), enabling specific targeting by neoantigen vaccine-primed host immunity. When integrated with neoantigen vaccination, the engineered viruses exhibited potent cytolytic activity in a variety of tumor models irrespective of the neoantigen expression profiles, eliciting robust systemic antitumor immunity to reject tumor rechallenge and inhibit abscopal tumor growth with a favorable safety profile. Thus, this study provides a powerful approach to enhance the universality and efficacy of neoantigen vaccines, meeting the urgent need for universal neoantigen vaccines in the clinic to facilitate the further development of tumor immunotherapy. Oncolytic adenovirus was engineered for the forced ectopic delivery of peptide-MHC ligand of T cell receptors (TCRs) to expand the universality and therapeutic efficacy of neoantigen vaccines in solid tumors. Transfer of peptide-MHC complexes redirected the cytotoxicity of vaccine-primed T cells towards tumor cells irrespective of the neoantigen expression profiles. Intratumoral treatment of the recombinant viruses safely and effectively suppressed tumor growth in mouse models by integrating with neoantigen vaccination or adoptive transferring vaccine-primed T cells. Intratumoral infiltration of neoantigen-specific CD8+ T cells was responsible for the therapeutic benefit of the integrative therapy. The applicability of the therapeutic strategy was validated in human-related design by using HLA-A*02:01 allele and HLA-A*02:01-restricted neoantigens. Transfer of peptide-MHC complexes redirected the cytotoxicity of vaccine-primed T cells towards tumor cells irrespective of the neoantigen expression profiles. Intratumoral treatment of the recombinant viruses safely and effectively suppressed tumor growth in mouse models by integrating with neoantigen vaccination or adoptive transferring vaccine-primed T cells. Intratumoral infiltration of neoantigen-specific CD8+ T cells was responsible for the therapeutic benefit of the integrative therapy. The applicability of the therapeutic strategy was validated in human-related design by using HLA-A*02:01 allele and HLA-A*02:01-restricted neoantigens. Oncolytic adenovirus was engineered for the forced ectopic delivery of peptide-MHC ligand of T cell receptors (TCRs) to expand the universality and therapeutic efficacy of neoantigen vaccines in solid tumors.