The Importance of Timing in Immunotherapy: A Systematic Review

Cancer remains a significant global health concern, with conventional treatments such as surgery, chemotherapy, and radiation posing considerable risks. In recent years, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a first-line treatment. ICIs enhance the immune system's ability to target and destroy cancer cells by blocking inhibitory proteins on T-cells. The body's circadian clock regulates essential biological functions, including immune response and metabolism, and its disruption can create an immunosuppressive environment conducive to tumor progression. Chronotherapy, which examines the influence of circadian rhythms on treatment efficacy, presents a promising approach to optimizing immunotherapy outcomes. This systematic review explores whether the timing of immunotherapy administration affects key patient outcomes, including overall survival (OS), progression-free survival (PFS), response rates, and mortality. A total of 21 studies involving 3,682 patients with a mean age of 64.7 were analyzed. Immunotherapy was administered for various cancers, the most common being melanoma, non-small cell lung cancer, and renal cell carcinoma. Only ICIs were considered, including monotherapies of nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, camrelizumab, tislelizumab, sintilimab, and combination therapies of nivolumab plus ipilimumab or ICIs with additional agents such as atezolizumab with bevacizumab or pembrolizumab with axitinib. Infusion timing varied across studies, with cutoff points for early versus late administration ranging from 11:37 to 16:30, the most common being 16:30. Most studies reported improved OS and PFS in patients receiving earlier infusions, with survival benefits ranging from +2.7 to +26.6 months, with a mean of +15.1 months, and PFS extensions from -0.5 to +28.3 months, with a mean of +8.1 months. Additionally, complete and partial response rates were higher in early infusion groups. However, findings on mortality rates were inconsistent. These results suggest that the timing of immunotherapy administration may significantly impact treatment efficacy, potentially due to interactions with circadian rhythms. Further research is needed to establish standardized guidelines for optimizing infusion timing to enhance patient outcomes.