Due to globally low seroprevalence in humans and elicitation of CTL responses of exceptional magnitude and longevity, attenuated arenavirus vectors that express tumor antigens are attractive cancer vaccine candidates. Bonilla et al. primed tumor-bearing mice with tumor antigen-expressing attenuated arenavirus vectors, and then switched to distantly related arenavirus vectors for the boost. This switch resulted in post-boost avoidance of secondary T cell responses to immunodominant vector epitopes, enhanced frequency of tumor-recognizing CTLs, increased survival with immunological memory, and the breaking of self-tolerance to tumor antigens.
Contributed by Margot O’Toole
ABSTRACT: Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8+ 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.
Author Info: (1) University of Basel, Department of Biomedicine, Basel, Switzerland (2) Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland (3) Hookipa Pharma Inc.
Author Info: (1) University of Basel, Department of Biomedicine, Basel, Switzerland (2) Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland (3) Hookipa Pharma Inc., Vienna, Austria (4) Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany (5) Tumor Immunology, Department for BioMedical Research, University of Bern, Bern, Switzerland (6) Institute of Virology, University of Zurich, Zurich, Switzerland (7) Division of Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland (8) Medical Oncology, University Hospital Basel, Basel, Switzerland (9) Present address: Diagnostics Information Solution, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel, Switzerland (10) These authors contributed equally (11) Lead contact *Correspondence: daniel.pinschewer@unibas.ch
