Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome

Abstract

Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1–5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

“…Some antagonists to inflammatory cytokines also decrease the toxicity [43]. Recently, selfamplifying catecholamine loop was found as a self-amplifier of CRS, and inhibiting key steps in the catecholamine synthesis pathway with metyrosine effectively reduced the CRS toxicity in mouse [93].…”

Cellular therapy: Immune‐related complications

“…Dasatinib can also inhibit T‐cell proliferation and thus may impact efficacy of CAR‐T. Catecholamine blockade is also being investigated to reduce CRS toxicities . Recent data on the use of lenzilumab, a monoclonal anti‐granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) has shown that in a murine model it is efficacious in preventing the progression of CRS .…”

“…Catecholamine blockade is also being investigated to reduce CRS toxicities. 74 Recent data on the use of lenzilumab, a monoclonal anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown that in a murine model it is efficacious in preventing the progression of CRS. 75 Similarly, studies have recently shown that IL-1 directed therapy with anakinra, a monoclonal anti-IL1 antibody, can also ameliorate progression of CRS in mouse models.…”

Pathogen Infection Recovery Probability (PIRP) Versus Proinflammatory Anti-Pathogen Species (PIAPS) Levels: Modelling and Therapeutic Strategies

“…Certain APS (such as certain pathogen specific antibodies) are expected to remain at their equilibrium levels for certain period of time so the same pathogen infection can be prevented or inhibited (principle of vaccination), though antibody equilibrium level slow decay in long period of time are normal or expected [13][14][15][16][17]. However, in certain immunodysfunction disorders, particularly certain hyperinflammatory disorders, such as cytokine release syndromes (CRS) or cytokine storm (CS) [4][5][6][7][8][9][10][11][12], macrophage activation syndromes (MAS) or macrophage-cytokine self-amplifying loop (MCSAL) [11], WBS proliferative disorders [4], certain PIAPS can grow out of control or not being efficiently dampened by the host anti-inflammatory species (e.g., IL-10) even after te where the pathogen may have been eliminated. It has been known that a number of PIAPS attack or damage normal or healthy cells resulting in tissue death (gangrene) and multiple organ dysfunctions or failures [2,[4][5][6][7][8][9][10][11][12][18][19][20].…”

“…Based on this model, the PIRP-PIAPS curve are divided into two stages: 1) Stage I or the PIRP rising stage corresponds to pathogen/APS evolution time period between t0 to te as shown in Figure 1: The PIRP of the pathogen infected host starts to rise as the host normal immune response generated APS (including PIAPS) are growing efficiently from initial levels of x0 (x0 can be zero for pathogen specific APS) and eventually approaching and maintaining at their equilibrium levels xe (blue solid line) where the pathogens are being eliminated or cleared. 2) Stage II or the PIRP descending stage: The PIAPS level further grow beyond their equilibrium levels xe as represented by the long dashed blue line (representing immunodysregulation such as hyperinflammatory disorders) [2,[4][5][6][7][8][9][10][11][12][18][19][20], the PIRP descends presumably due to excessive PIAPS start to damage the normal or healthy tissues or organs. Eventually the PIRP could descend to a very low level due to heavy damages of tissues (particularly lung tissues) that could result in multiple organ failures [2,[7][8][9][10][11][12][18][19][20].…”