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A replicating LCMV-based vaccine for the treatment of solid tumors.

Molecular therapy : the journal of the American Society of Gene Therapy

Authors: Mette-Triin Purde, Jovana Cupovic, Yannick A Palmowski, Ahmad Makky, Sarah Schmidt, Alexander Rochwarger, Fabienne Hartmann, Felix Stemeseder, Alexander Lercher, Marie-Therese Abdou, David Bomze, Lenka Besse, Fiamma Berner, Thomas Tüting, Michael Hölzel, Andreas Bergthaler, Stefan Kochanek, Burkhard Ludewig, Henning Lauterbach, Klaus K Orlinger, Tobias Bald, Andrea Schietinger, Christian M Schürch, Sandra S Ring, Lukas Flatz

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 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.

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

PMID: 38058126

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