by akronbiotech

Recently published research findings suggest that we may be able to prevent Cytokine Release Syndrome (CRS) through the oral administration of an FDA-approved drug. CAR-T therapy is a promising new approach to cancer treatment. However, a devastating side effect of CAR-T cell infusion is CRS. The patient’s infused activated T cells release interferon gamma (IFN-γ) and/or tumor necrosis factor alpha (TNF-α), which leads to the activation of macrophages and other immune cells. These cells release large amounts of pro-inflammatory cytokines that can jeopardize the patient’s life. Specifically, macrophages and other immune cells can release large amounts of IL-6, which creates a positive feedback loop, activating T cells and other immune cells. This leads to CRS, and in severe cases, causes organ failure and death. Patients receiving cell therapy that experience CRS are often treated with an anti-IL6R antibody (tocilizumab), which blocks IL-6 signaling. Nevertheless, tocilizumab may not shut CRS down completely, as it cannot cross the blood-brain barrier, thereby stopping CRS in the central nervous system. Furthermore, tocilizumab is often employed once it is too late to effectively treat CRS.

A newly published study (1,2) finds that catecholamines (such as epinephrine) limit CRS caused by CAR-T therapy and further, that blocking catecholamine synthesis prevents CRS. In this study, scientists treat tumor-bearing mice with a bacterium called Clostridium novyi-NT. These Bacteria kill the tumor, but cause CRS in the process, resulting in death. Mice that are pre-treated with agents that downregulate inflammatory effect such as IL6-R blockage produce only a marginal effect on survival rate. The researchers then engineer an anti-inflammatory protein ANP (Atrial natriuretic peptide) expressed in bacteria. Surprisingly, they find that these bacteria not only kill the tumor, but also alleviate CRS, increasing the survival rate. Moreover, they find that ANP reduces cytokine release by inhibiting catecholamine synthesis from macrophages. To further prove the idea, scientists use metyrosine (MTR) to block catecholamine synthesis. Mice that are pre-treated with MTR see increased survival rates after the induction of CRS.  This indicates a possible avenue for preventing CRS. Since the FDA has already approved ANP for the treatment of acute heart failure and kidney disease and MTR for the treatment of hypertension, we can anticipate that these drugs will be safe for patients receiving cell therapies.  It will be exciting to see whether these drugs are able to alleviate CRS in the clinical setting.

 

 

  1. https://www.nature.com/articles/d41586-018-07581-w
  2. https://www.nature.com/articles/s41586-018-0774-y


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