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New Approach to Treat Patients with Checkpoint Inhibitor-induced Adverse Events (Apostolova Lab)
In a collaborative effort, Petya Apostolova and colleagues found a way to combat immune-related adverse events during immune checkpoint inhibitor treatment, here shown in action. (Image: Adobe Stock, KI)
Immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA4 antibodies, enhance anti-cancer immunity and are a potent treatment for several types of cancer. However, overt activation of the immune system can also cause severe immune-related adverse effects (irAE) - autoimmune disorders that affect various organs in the body, such as the skin, the gastrointestinal tract, and the liver. Immunosuppressive drugs are used to treat irAE, but some patients require long-term use, which might compromise anti-tumor immunity. Developing novel approaches to cure irAE might help improve the outcomes for patients treated with ICI.
Extracorporeal photopheresis (ECP) is a procedure in which the patient's white blood cells are collected, combined with a photosensitizer, exposed to UV light, and reinfused in the patient. While this intervention has been used as an immunomodulatory approach for graft-versus-host disease and certain autoimmune disorders, its mechanism of action remains poorly understood. Building on their previous work (doi: 10.1056/NEJMc1912274), researchers led by Petya Apostolova and Robert Zeiser (Medical Center - University of Freiburg, Germany), with first author Lukas Braun, now report that ECP is an efficient and safe treatment for patients with irAEs.
In their latest study, published in the journal Cancer Cell, the authors performed a phase-1b/2 clinical trial (EudraCT-No.2021-002073-26), enrolling 14 patients with ICI-induced colitis, hepatitis, or dermatitis. ECP showed an excellent safety profile and induced an overall response rate for all irAEs of 92%. In a second real-world cohort of patients treated at four different academic centers, responses to ECP were observed in 81.8% of the patients. Molecular preclinical studies surprisingly revealed that the molecule adiponectin, mainly known as a protein secreted predominantly by adipose tissue, played an essential role in mediating the effects of ECP. ECP induced local intestinal adiponectin production, leading to a reduction of pro-inflammatory T cells in irAE-affected organs, while sparing anti-tumor immunity. Taken together, the study establishes an ECP-adiponectin axis that specifically shapes tissue immune responses to overcome ICI-induced irAE. These findings pave the way for the establishment of ECP as a safe and efficient treatment for patients with irAE.
The study was the result of a strong collaboration effort of many physicians and scientists in Freiburg, Basel, and several academic centers in Germany, Switzerland, and the USA.