Cytokine Release Syndrome Associated With Immune-Modulating Chemotherapy: Potential Mitigating Role of Intravenous Omega-3 Fatty Acid Triglycerides.

Abstract

Patient susceptibility to cytokine release syndrome (CRS) resulting from immune-modulating chemotherapy has profound implications for clinical outcome. This is particularly true for patients receiving CAR T-cell therapy. First-line pharmacotherapy for CRS includes the administration of the IL-6 receptor-binding monoclonal antibody tocilizumab, or tocilizumab and corticosteroids. Other agents, such as siltuximab, anakinra, and dasatinab are also being explored for refractory cases of CRS. This review summarizes the potential role of omega-3 fatty acids, that is, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at ameliorating CRS in cancer patients receiving immune-modulating chemotherapy, and is compared with current treatment strategies to reduce the severity of the inflammatory response. Selective blockade of specific proinflammatory mediators (e.g., IL-6) is effective, but carries a significant risk of serious opportunistic infections. In contrast, omega-3 fatty acids affect multiple triggers underlying the inflammatory response (i.e., prostaglandins, leukotrienes, transcription factors, and specialized proresolving molecules), and its major limitation is avoidance of hypertriglyceridemia, which can be managed by reducing the rate of intravenous administration. This discussion proposes a novel approach by continuous infusion of omega-3 fatty acids to modulate the intensity of the severe systemic inflammatory response from CRS. The purpose of this review is to highlight the potential clinical benefits of a specialized omega-3 fatty acids dosage form to mitigate the severity of CRS as a hypothetical alternative to current treatment. Optimizing the formulation, for example, enriched fish oil that meets drug concentration standards for EPA and DHA, a continuous infusion rate, reductions in long-chain saturated fatty acids concentrations, and addition of medium-chain triglycerides to improve EPA + DHA utilization and physical stability are key pharmaceutical factors. This may result in a safer and more effective option than targeted abrogation of cytokines and consequent risks of adverse drug reactions, but will require formal study in randomized control trials in humans.