A replicating LCMV-based vaccine for the treatment of solid tumors Journal Article
| Authors: | Purde, M. T.; Cupovic, J.; Palmowski, Y. A.; Makky, A.; Schmidt, S.; Rochwarger, A.; Hartmann, F.; Stemeseder, F.; Lercher, A.; Abdou, M. T.; Bomze, D.; Besse, L.; Berner, F.; Tüting, T.; Hölzel, M.; Bergthaler, A.; Kochanek, S.; Ludewig, B.; Lauterbach, H.; Orlinger, K. K.; Bald, T.; Schietinger, A.; Schürch, C.; Ring, S. S.; Flatz, L. |
| Article Title: | A replicating LCMV-based vaccine for the treatment of solid tumors |
| Abstract: | Harnessing the immune system to eradicate tumors requires identification and targeting of tumor antigens, including tumor-specific neoantigens and tumor-associated self-antigens. Tumor-associated antigens are subject to existing immune tolerance, which must be overcome by immunotherapies. Despite many novel immunotherapies reaching clinical trials, inducing self-antigen-specific immune responses remains challenging. Here, we systematically investigate viral-vector-based cancer vaccines encoding a tumor-associated self-antigen (TRP2) for the treatment of established melanomas in preclinical mouse models, alone or in combination with adoptive T cell therapy. We reveal that, unlike foreign antigens, tumor-associated antigens require replication of lymphocytic choriomeningitis virus (LCMV)-based vectors to break tolerance and induce effective antigen-specific CD8+ T cell responses. Immunization with a replicating LCMV vector leads to complete tumor rejection when combined with adoptive TRP2-specific T cell transfer. Importantly, immunization with replicating vectors leads to extended antigen persistence in secondary lymphoid organs, resulting in efficient T cell priming, which renders previously “cold” tumors open to immune infiltration and reprograms the tumor microenvironment to “hot.” Our findings have important implications for the design of next-generation immunotherapies targeting solid cancers utilizing viral vectors and adoptive cell transfer. © 2023 The Author(s) |
| Keywords: | controlled study; human cell; nonhuman; solid tumor; cd8+ t lymphocyte; t lymphocyte; animal cell; mouse; cancer immunotherapy; melanoma; animal experiment; animal model; tumor antigen; immunological tolerance; regulatory t lymphocyte; immune response; cancer vaccine; drug combination; antigen specificity; cancer immunization; autoantigen; adoptive transfer; effector cell; virus replication; cancer control; tumor rejection; adoptive immunotherapy; vaccine; cell transfer; lymphoid organ; virus vector; immunization; adoptive cell transfer; tumor microenvironment; lymphocytic choriomeningitis virus; self-antigens; human; male; article; solid malignant neoplasm; viral-vector-based vaccines; vector vaccine |
| Journal Title: | Molecular Therapy |
| Volume: | 32 |
| Issue: | 2 |
| ISSN: | 1525-0016 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-02-07 |
| Start Page: | 426 |
| End Page: | 439 |
| Language: | English |
| DOI: | 10.1016/j.ymthe.2023.11.026 |
| PUBMED: | 38058126 |
| PROVIDER: | scopus |
| PMCID: | PMC10861942 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
