While immune checkpoint inhibitors (ICIs) can produce durable responses in some cancer patients, their use is frequently associated with immune-related adverse events (irAEs).

These events involve off-target inflammatory damage to normal tissues, resembling autoimmune reactions.

Up to 95% of patients treated with combination PD-1/CTLA-4 blockade experience irAEs, with 30–50% of these being severe, often requiring ICI discontinuation and systemic immunosuppression. 

Approximately 1–1.5% of patients may die from irAEs, and non-fatal irAEs can lead to significant morbidity, such as endocrine gland destruction necessitating lifelong hormone replacement therapy. There is a critical need to mitigate these adverse effects. However, the molecular mechanisms underlying irAEs are poorly understood, and no reliable biomarkers exist for predicting these events.

To address this EXACT study aims to provide a comprehensive understanding of the pathogenesis and risk factors of immune-related adverse events (irAEs) in patients undergoing immune checkpoint inhibitor (ICI) therapy. This will be achieved through the collection and multimodal profiling of patients biological samples, integrated with detailed clinical data.

The ultimate goal is to identify biomarkers and develop strategies to predict, prevent and manage irAEs, thereby improving the safety and efficacy of ICI therapies and enhancing patient outcomes.

Patients undergoing immunotherapy

This figure highlights the differences between patients who develop immune-related adverse events (irAE) and those who do not. The flowchart breaks down the monitoring process from baseline through the treatment cycles, detailing sample collections and specific actions taken at each stage.

his image provides a detailed monitoring process for patients undergoing immunotherapy, highlighting the differences between patients who develop immune-related adverse events (irAE) and those who do not. The flowchart breaks down the monitoring process from baseline through the treatment cycles, detailing sample collections and specific actions taken at each stage.

Figure 1: Patients without irAE

Baseline: Blood and stool samples are collected.
Cycle 2: Blood samples are collected to monitor the patient's condition and response.
Cycle 4: Blood samples are collected. Skin biopsy if no rash is present.
Every 4 cycles: Blood samples are collected to continually monitor response.
End of treatment: Blood samples are collected to assess treatment outcome.
Follow-up (every 3 months): Regular blood samples are collected to monitor long-term response and delayed effects.

Patients with irAE: Baseline: Blood and stool samples are collected. Cycle 2: Blood samples are collected to check for early signs of irAE. Cycle 4: Blood samples are collected. Skin biopsy if no rash is present. Onset of irAE: Blood samples, stool samples (if colitis), and skin biopsy (if rash) are collected.

Figure 2: Patients with irAE

Baseline: Blood and stool samples are collected.
Cycle 2: Blood samples are collected to check for early signs of irAE.
Cycle 4: Blood samples are collected. Skin biopsy if no rash is present.
Onset of irAE: Blood samples, stool samples (if colitis), and skin biopsy (if rash) are collected.
Increasing severity of irAE: Extensive sampling and testing: blood samples, additional stool samples (if colitis), additional skin biopsies (if rash), and other affected tissue biopsies.
Resolution of irAE: Blood samples, stool samples (if colitis), and skin biopsies (if rash) are collected to confirm resolution and recovery.
End of treatment and follow-up (every 3 months): Blood samples are collected to ensure there are no lingering effects or recurrence of irAE.

Funding

  • The Royal Marsden Cancer Charity
  • NIHR Biomedical Research Centre at the Institute of Cancer Research and Royal Marsden Hospital
  • Medical Research Council
  • British Skin Foundation
  • Francis Crick Institute Translational Fund

Collaborators

  • The Royal Marsden Hospital NHS Foundation Trust
  • IMU Biosciences
  • Health Economics Unit, City, University of London