Publikation
A replicating LCMV-based vaccine for the treatment of solid tumors.
Wissenschaftlicher Artikel/Review - 05.12.2023
Purde Mette-Triin, Cupovic Jovana, Palmowski Yannick A, Makky Ahmad, Schmidt Sarah, Rochwarger Alexander, Hartmann Fabienne, Stemeseder Felix, Lercher Alexander, Abdou Marie-Therese, Bomze David, Besse Lenka, Berner Fiamma, Tüting Thomas, Hölzel Michael, Bergthaler Andreas, Kochanek Stefan, Ludewig Burkhard, Lauterbach Henning, Orlinger Klaus K, Bald Tobias, Schietinger Andrea, Schürch Christian M, Ring Sandra Stephanie, Flatz Lukas
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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.