Dexamethasone premedication suppresses vaccine-induced immune responses against cancer

Vormehr, Mathias; Lehar, Sophie M.; Kranz, Lena M.; Tähtinen, Siri; Oei, Yoko; Javinal, Vincent; Delamarre, Lélia; Walzer, Kerstin C; Diken, Mustafa; Kreiter, Sebastian; Mellman, Ira; Şahin, Uğur; Schartner, Jill; Türeci, Özlem

doi:10.1080/2162402x.2020.1758004

Cited by 20 publications

(16 citation statements)

References 46 publications

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“…Data on the effect of steroids on mRNA vaccine-induced antigen-specific T cell response are limited. One study demonstrated that dexamethasone given before, but not after, an mRNA-based cancer vaccine resulted in reduced activation of antigen-specific T cells 6 . In the case under study, steroids were administered 10 d after vaccination and unlikely to have affected vaccine-specific immune response.…”

Section: Mainmentioning

confidence: 99%

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2

Fendler

Shepherd

et al. 2021

Nat Med

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Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population.

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Section: Mainmentioning

confidence: 99%

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2

Fendler

Shepherd

et al. 2021

Nat Med

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“…While this has led to significant differences in distribution, sensitivity and ligand specificity of PRRs, it has also resulted in differentiating evolutionary strategies for resistance and tolerance between humans and mice 33 . Relative to human response, mice have been found to be extremely resilient to different inflammatory stimuli 18,19,33 , including RNA-LPX vaccines 13,17 . In this study, we demonstrated that vaccine-induced systemic inflammatory responses are driven by IL-1 and antagonized by endogenous IL-1ra, and that these findings can be generalized to other forms of innate immune stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to humans, C57BL/6 and Balb/c mice are remarkably tolerant to RNA vaccines and only display limited systemic cytokine release following intravenous (IV) administration of liposomal, unmodified RNA (RNA-LPX) vaccine 13,17 . Even at doses of RNA (50µg) that are well-tolerated in mice, patients exhibit transient mild to moderate flulike symptoms that constrain dose exploration to a narrow range and possibly limit optimal T cell responses 6,8,9 .…”

Section: Main Textmentioning

confidence: 99%

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IL-1β and IL-1ra are key regulators of the inflammatory response to RNA vaccines

Mellman¹,

Tähtinen²,

Tong³

et al. 2021

Preprint

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Excessive systemic inflammation is characteristic to various acute conditions including sepsis, viral infections and immunotherapy-induced adverse events such as cytokine release syndrome (CRS). Recently, several clinical trials evaluating variants of lipid-formulated RNA vaccines for either cancer or COVID-19 have reported systemic inflammatory responses that limit vaccine dosing in humans. Preclinical studies in inbred laboratory mice failed to predict these adverse events, suggesting the existence of underlying differences in sensitivity to Toll-like receptor (TLR) or other innate agonists between humans and mice. Here, we identify interleukin 1 receptor antagonist (IL-1ra) as an endogenous, inducible suppressor of systemic inflammation. In humans, stimulation with a TLR7/8 adjuvanted RNA-lipoplex (RNA-LPX) vaccine results in the secretion of inflammasome-activated interleukin-1β (IL-1β) by monocytes. Remarkably, IL-1β was found to control the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6) associated with CRS. Unlike humans, murine leukocytes preferentially upregulate anti-inflammatory IL-1ra relative to IL-1β. IL-1ra deletion in mice leads to CRS-like symptoms, indicating that high levels of IL-1ra protect mice from uncontrolled systemic inflammation. Our results demonstrate that IL-1β and IL-1ra are key regulators that control systemic responses to RNA vaccines and other inflammatory stimuli. These data provide an explanation for the dramatic difference in dose-dependent tolerability between mice and humans and suggest an approach to evaluate pathogen-induced or immunotherapy-related inflammatory toxicities in vivo.

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“…As would be expected, these effects are not target cell specific and would also be apparent outside of anti-tumor immunity. Indeed, premedication of tumor-bearing mice with Dex inhibited vaccine-dependent induction of serum cytokines and chemokines and reduced both the number and the activation of conventional DCs expressing vaccine encoded antigens [52], suggesting that induction therapy with Dex alone might impair off-target immune responses. In fact, protocols involving Dex are a risk factor for infection in MM patients undergoing induction therapy [27].…”

Section: Dexamethasonementioning

confidence: 99%

The Impact of Induction Regimes on Immune Responses in Patients with Multiple Myeloma

Firer

Shapira

Luboshits

2021

Cancers

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Current standard frontline therapy for newly diagnosed patients with multiple myeloma (NDMM) involves induction therapy, autologous stem cell transplantation (ASCT), and maintenance therapy. Major efforts are underway to understand the biological and the clinical impacts of each stage of the treatment protocols on overall survival statistics. The most routinely used drugs in the pre-ASCT “induction” regime have different mechanisms of action and are employed either as monotherapies or in various combinations. Aside from their direct effects on cancer cell mortality, these drugs are also known to have varying effects on immune cell functionality. The question remains as to how induction therapy impacts post-ASCT immune reconstitution and anti-tumor immune responses. This review provides an update on the known immune effects of melphalan, dexamethasone, lenalidomide, and bortezomib commonly used in the induction phase of MM therapy. By analyzing the actions of each individual drug on the immune system, we suggest it might be possible to leverage their effects to rationally devise more effective induction regimes. Given the genetic heterogeneity between myeloma patients, it may also be possible to identify subgroups of patients for whom particular induction drug combinations would be more appropriate.

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Dexamethasone premedication suppresses vaccine-induced immune responses against cancer

Cited by 20 publications

References 46 publications

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2

IL-1β and IL-1ra are key regulators of the inflammatory response to RNA vaccines

The Impact of Induction Regimes on Immune Responses in Patients with Multiple Myeloma

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