Chrono-immunotherapy as a low-hanging fruit for cancer treatment? A call for pragmatic randomized clinical trials

Abstract

The share of immune checkpoint inhibitors (ICIs) used in cancer treatment has rapidly increased in recent years. Although ICIs have the potential to provide a durable survival benefit in a subset of patients, many patients do not respond to these costly and often toxic therapies.Recent retrospective clinical data indicate that the time of day of ICI infusion may be a powerful modulator of their efficacy. These observational studies suggest an enhanced efficacy of morning over evening infusion. However, randomized trials have not confirmed in other fields findings obtained by observational studies, possibly because of selection bias and residual confounding factors. Thus, while the data are intriguing, the time dependence of the efficacy of immunotherapy needs to be confirmed in pragmatic randomized clinical trials. Here, we provide an overview of the modulation of ICI efficacy by the timing of immunotherapy infusion and critically discuss the biological rationale for chrono-immunotherapy, the circadian regulation of the immune system, and the need for pragmatic randomized clinical trials to confirm an effect of the timing of immunotherapy infusions on patient outcomes.

Keywords: Immune Checkpoint Inhibitor; Immunotherapy; Infusion.

Figure 1. Circadian regulation of the cancer immunity cycle. Multiple steps of the cancer immunity cycle are subjected to circadian oscillations. The molecules and cell types affected in their expression and abundance, respectively, are indicated by a clock symbol. Please note that although DC trafficking to the tumor draining lymph is altered depending on the time of day, the indicated molecules (CCR7, CCL21, LYVE-1, CD99 and JAM-A) have formally not been investigated in the tumor setting. However, the circadian regulation of their expression has been shown in the immunosurveillance of the skin. DC, dendritic cell; MDSC, myeloid-derived suppressor cell.