Melatonin as an immunomodulator in CD19-targeting CAR-T cell therapy: managing cytokine release syndrome

Abstract

Background Chimeric antigen receptor CAR-T cell therapies have ushered in a new era of treatment for specific blood cancers, offering unparalleled efficacy in cases of treatment resistance or relapse. However, the emergence of cytokine release syndrome (CRS) as a side effect poses a challenge to the widespread application of CAR-T cell therapies. Melatonin, a natural hormone produced by the pineal gland known for its antioxidant and anti-inflammatory properties, has been explored for its potential immunomodulatory effects. Despite this, its specific role in mitigating CAR-T cell-induced CRS remains poorly understood. Methods In this study, our aim was to investigate the potential of melatonin as an immunomodulatory agent in the context of CD19-targeting CAR-T cell therapy and its impact on associated side effects. Using a mouse model, we evaluated the effects of melatonin on CAR-T cell-induced CRS and overall survival. Additionally, we assessed whether melatonin administration had any detrimental effects on the antitumor efficacy and persistence of CD19 CAR-T cells. Results Our findings demonstrate that melatonin effectively mitigated the severity of CAR-T cell-induced CRS in the mouse model, leading to improved overall survival outcomes. Remarkably, melatonin administration did not compromise the antitumor effectiveness or persistence of CD19 CAR-T cells, indicating its compatibility with therapeutic goals. These results suggest melatonin's potential as an immunomodulatory compound to alleviate CRS without compromising the therapeutic benefits of CAR-T cell therapy. Conclusion The study's outcomes shed light on melatonin's promise as a valuable addition to the existing treatment protocols for CAR-T cell therapies. By attenuating CAR-T cell-induced CRS while preserving the therapeutic impact of CAR-T cells, melatonin offers a potential strategy for optimizing and refining the safety and efficacy profile of CAR-T cell therapy. This research contributes to the evolving understanding of how to harness immunomodulatory agents to enhance the clinical application of innovative cancer treatments.

Mechanism of Action of Melatonin as a Potential Adjuvant Therapy in Inflammatory Bowel Disease and Colorectal Cancer

“…Discontinuous sleeping and stressful situations were found to increase the number of M1 macrophages [165], suggesting a potential role for melatonin on this axis. This was confirmed by some studies where melatonin significantly decreased M1-Macrophages and attenuated their pro-inflammatory response [166]. This effect was established by the activation of STAT3 signaling responsible for the accumulation and activation of immunosuppressive cells (e.g: Treg, Th17) [167].…”

A Review of CAR-T Combination Therapies for Treatment of Gynecological Cancers

“…Severe or prolonged adverse events due to immune overactivation can be managed by the utilization of immunomodulators such as tocilizumab or corticosteroid therapy. Additionally, Zheng et al suggest that melatonin can be used as an effective immunomodulator for mitigation of CAR-T-induced cytokine release syndrome without compromising the anti-tumor activity of CAR-T [ 69 ]. Therefore, it can be suggested for use in combination therapy as well.…”