Arenavirus vectors for massive tumor self-antigen-specific CD8 T cell attack

• Published in: The Journal of immunology (1950) 2020-05, Vol.204 (1_Supplement), p.169-169.13
• Main Authors: Pinschewer, Daniel D., Bonilla, Weldy V., Kallert, Sandra, Kirchhammer, Nicole, Marx, Anna-Friederike, Krzyzaniak, Magdalena, Schmidt, Sarah, Raguz, Josipa, Berka, Ursula, Günther, Stephan, Magnus, Carsten, Orlinger, Klaus, Zippelius, Alfred
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.204.Supp.169.13

Therapeutic vaccination regimens inducing high frequencies of clinically effective tumor-targeting CD8 T cells represent an unmet need in cancer immunotherapy. We exploit cutting-edge viral reverse genetics to harness the immunostimulatory properties of the arenaviruses Pichinde virus and lymphocytic choriomeningitis virus for therapeutic cancer vaccination. When administering to mice life-replicating vector formats of these two viruses, both delivering the same cancer testis self-antigen in a heterologous prime-boost regimen, tumor-specific CD8 T cell responses reached up to 50% of the circulating CD8 T cell pool. This massive CD8 T cell attack eliminated established solid tumors in a significant proportion of animals, accompanied by complete protection against tumor re-challenge. The magnitude of CD8 T cell responses was driven by alarmin signals and depended on the combined use of two genealogically distantly related arenaviruses. Combinations of closely related vectors or the repeated administration of the same vector were not inhibited by vector-neutralizing antibodies, but CD8 T cell immunodominance hierarchies favored vector backbone-targeted responses at the expense of self-reactive T cell specificities. These findings establish a powerful arenavirus-based tumor immunotherapy regimen exploiting key innate signaling pathways and reshuffling immunodominance hierarchies to break tumor self-directed tolerance