Unraveling immune checkpoint inhibitor induced toxicity

In the past years, experience with immune checkpoint inhibition has substantially increased. Initially, this mode of immunotherapy lead to unprecedented results in terms of progression-free and overall survival in metastasized melanoma and non-small cell lung cancer. Nowadays, indications for immune checkpoint inhibition (anti-PD-(L)1, anti-CTLA-4 or both targets combined) are being expanded.

On the contrary, this success comes with a considerable burden of adverse events that will affect many patients to some extent. Up to 55 percent of patients experience severe (grade 3 or higher) toxicity. Under normal circumstances, activating and inhibiting signals maintain a delicate balance in the immune system’s activation status, yet immune checkpoint inhibition disturbs this equilibrium towards an overactive state. This may result in inflammation of healthy tissue, like skin, gut, or thyroid gland. Theoretically, inflammation can occur in any tissue or organ. All together, these inflammatory events are known as immune-related adverse events (irAEs).

The pathogenesis underlying irAEs is far from completely understood. It is strongly suggested that the course of toxicity depends on the exact type of checkpoint inhibition, tumor- and tissue characteristics and patient factors, such as composition of intestinal microbiome. As a result of incomplete understanding, treatment of irAEs is mostly empirically driven and usually corticosteroids constitute the first line of treatment. Besides the lack of specificity concerned with corticosteroids, some studies suggest this therapy counteracts anti-tumor effects of checkpoint inhibition.

In my PhD trajectory I will investigate the exact mechanisms underlying irAEs, using a variety of techniques including tissue mass cytometry (tissue CyTOF), biomarker platform Luminex, RNA-Seq and TCR-Seq. Experiments will be conducted with human material (plasma, PBMCs, feces and tissue biopsies) stored in the UMC Utrecht biobank from patients treated with immune checkpoint inhibition included in the UNICIT cohort. In this way, this project will contribute to a better understanding of immune checkpoint inhibition related toxicity and a more targeted approach in its treatment, whilst maintaining the anti-tumor efficacy of immune checkpoint blockade.

Mick van Eijs