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

• Published in: Molecular therapy Vol. 32; no. 2; pp. 426 - 439
• Main Authors: 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 S., Flatz, Lukas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.02.2024; American Society of Gene & Cell Therapy
• Subjects: adoptive cell transfer; Animals; Antigens, Neoplasm - genetics; Autoantigens; cancer immunotherapy; Cancer Vaccines; CD8-Positive T-Lymphocytes; Lymphocytic choriomeningitis virus - genetics; melanoma; Mice; Neoplasms - drug therapy; Original; self-antigens; Tumor Microenvironment; viral-vector-based vaccines; melanoma; cancer immunotherapy; self-antigens; adoptive cell transfer; viral-vector-based vaccines
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2023.11.026

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. [Display omitted] Flatz and colleagues investigate virus-based cancer vaccines encoding a tumor-associated self-antigen for treating established melanomas. The authors find that a tumor-associated antigen requires replication of the virus-based vaccine to induce an effective antitumor response. Combined with adoptive T cell transfer, immunization with a replicating virus-based vaccine leads to complete tumor rejection.