Dexamethasone premedication suppresses vaccine-induced immune responses against cancer. (1st January 2020)

• Record Type: Journal Article
• Authors: Vormehr, Mathias; Lehar, Sophie; Kranz, Lena M.; Tahtinen, Siri; Oei, Yoko; Javinal, Vincent; Delamarre, Lélia; Walzer, Kerstin C.; Diken, Mustafa; Kreiter, Sebastian; Mellman, Ira; Sahin, Ugur; Schartner, Jill M.; Türeci, Özlem
• Is Part Of: Oncoimmunology. Volume 9:Number 1(2020)
• Publication Date: 2020-01-01
• Subjects: Glucocorticosteroids -- dexamethasone -- T-cell vaccine -- RNA vaccine -- cancer immunotherapy -- T-cell priming; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2020.1758004
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: Glucocorticosteroids (GCS) have an established role in oncology and are administered to cancer patients in routine clinical care and in drug development trials as co-medication. Given their strong immune-suppressive activity, GCS may interfere with immune-oncology drugs. We are developing a therapeutic cancer vaccine, which is based on a liposomal formulation of tumor-antigen encoding RNA (RNA-LPX) and induces a strong T-cell response both in mice as well as in humans. In this study, we investigated in vivo in mice and in human PBMCs the effect of the commonly used long-acting GCS Dexamethasone (Dexa) on the efficacy of this vaccine format, with a particular focus on antigen-specific T-cell immune responses. We show that Dexa, when used as premedication, substantially blunts RNA-LPX vaccine-mediated immune effects. Premedication with Dexa inhibits vaccine-dependent induction of serum cytokines and chemokines and reduces both the number and activation of splenic conventional dendritic cells (cDC) expressing vaccine-encoded antigens. Consequently, priming of functional effector T cells and therapeutic activity is significantly impaired. Interestingly, responses are less impacted when Dexa is administered post-vaccination. Consistent with this observation, although many inflammatory cytokines are reduced, IFNα, a key cytokine in T-cell priming, is less impacted and antigen expression by cDCs is intact. These findings warrant special caution when combining GCS with immune therapies relying on priming and activation of antigen-specific T cells and suggest that careful sequencing of these treatments may preserve T-cell induction.