Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack

Weldy V Bonilla,Alfred Zippelius,Daniel D Pinschewer,Stephan Günther,Sandra M Kallert,Josipa Raguz,Min Lu,Sabine Hoepner,Ursula Berka,Stéphanie Darbre,Klaus K Orlinger,Ilena Vincenti,Romy Kerber,Sarah Schmidt,Doron Merkler,Carsten Magnus,Nicole Kirchhammer,Mindaugas Paužuolis ,Anna‐Friederike Marx ,Magdalena Anna Krzyzaniak

doi:10.1016/j.xcrm.2021.100209

Abstract

SummaryTherapeutic 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.

Highlights

Cytotoxic CD8+ T lymphocytes (CTLs) are central mediators of adaptive immunity
Contrary to commonly held concepts, anti-vector CTL responses rather than neutralizing antibody (nAb) curtail the immunogenicity of homologous arenavirus vector prime-boost vaccination
We vectorized additional mammalian arenaviruses to exploit their immunotherapeutic potential when combined in heterologous prime-boost combinations

Summary

Introduction

Cytotoxic CD8+ T lymphocytes (CTLs) are central mediators of adaptive immunity. Tumor-infiltrating CTLs in several tumor types are associated with clinical outcome,[1–3] and pre-existing CTL infiltration may predict responsiveness to immune checkpoint inhibition.[4]. CTLs are key players in HIV elite control and hepatitis B virus clearance.[5–7]. Therapeutic vaccination for CTL induction holds great promise for cancer therapy[8,9] but has delivered inconsistent therapeutic benefits, including failure of large clinical trials.[10–13]. Despite induction of sizeable tumor antigen-specific CD8+ T cell frequencies by modalities such as adjuvanted peptides,[14] inefficient tumor infiltration has curtailed the clinical efficacy of these cells.[15,16]. Delivering tumor-associated antigens (TAAs) in the context of virus-induced inflammation[17] has significant potential to overcome these hurdles. The immunostimulatory properties of the viral particles themselves, exhibiting pathogen-associated molecular patterns, activate antigen-presenting cells (APCs) to augment and differentiate immune responses.[26,27] Several viral vector platforms have been developed for therapeutic use against solid tumors.[13,18–25] The immunostimulatory properties of the viral particles themselves, exhibiting pathogen-associated molecular patterns, activate antigen-presenting cells (APCs) to augment and differentiate immune responses.[26,27]

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Discussion

Conclusion