Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack
Weldy V. Bonilla, Nicole Kirchhammer, Anna‐Friederike Marx, Sandra M. Kallert, Magdalena A. Krzyzaniak, Min Lu, Stéphanie Darbre, Sarah Schmidt, Josipa Raguz, Ursula Berka, Ilena Vincenti, Mindaugas Paužuolis, Romy Kerber, Sabine Hoepner, Stephan Günther, Carsten Magnus, Doron Merkler, Klaus K. Orlinger, Alfred Zippelius, Daniel D. Pinschewer
Abstract
T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control.