This observational study aims to comprehensively characterize immune-related adverse events (irAEs) occurring during immune checkpoint inhibitor (ICI) therapy in cancer patients and to evaluate the safety and clinical outcomes of ICI rechallenge following irAE resolution.

In addition to detailed clinical data collection, the study incorporates biospecimen acquisition, when clinically indicated and feasible, including peripheral blood and organ-specific specimens (e.g., bronchoalveolar lavage fluid for ICI-related pneumonitis, liver biopsy tissue for ICI-related hepatitis, and other relevant clinical specimens). These samples will support exploratory immunologic and molecular analyses to better understand mechanisms underlying irAE development, resolution, and recurrence after rechallenge.

This study is designed to generate real-world evidence to improve risk stratification, toxicity management, and decision-making regarding immunotherapy continuation or re-initiation.

1. Background Immune checkpoint inhibitors (ICIs), including anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents, have significantly improved survival outcomes across multiple malignancies. However, immune-related adverse events (irAEs), resulting from immune activation, frequently occur during ICI therapy and may involve multiple organ systems, including but not limited to the lung, liver, gastrointestinal tract, endocrine organs, heart, and other tissues.

   irAEs range in severity from mild to life-threatening and often require treatment interruption, immunosuppressive therapy, or permanent discontinuation of ICIs. Although clinical guidelines provide general management recommendations, substantial heterogeneity exists in irAE presentation, clinical course, recovery patterns, and long-term outcomes.

   In selected patients, re-initiation of ICIs after irAE resolution or stabilization is considered in clinical practice to maintain anti-tumor benefit. However, the recurrence risk, severity of recurrent irAEs, and associated clinical outcomes following ICI rechallenge remain incompletely defined. Additionally, the immunologic and tissue-level mechanisms underlying irAE development, resolution, and recurrence are not fully understood.

2. Study Objectives

   This observational cohort study aims to:

   ① Characterize the incidence, timing, organ involvement, severity (according to CTCAE criteria), management strategies, and clinical outcomes of irAEs occurring during ICI therapy in cancer patients.

   ② Evaluate the safety of ICI rechallenge after resolution or stabilization of irAEs, including recurrence rate, severity, time to recurrence, and oncologic outcomes.

   ③ Explore potential immunologic and molecular features associated with irAE onset, resolution, and recurrence through analysis of peripheral blood and organ-specific biospecimens when available.

3. Study Design This is an observational cohort study including cancer patients treated with ICIs at Peking Union Medical College Hospital (PUMCH).

   Eligible patients include those who receive ICI therapy and subsequently develop documented irAEs during treatment. Clinical data will be systematically collected, including:Baseline patient characteristics;Tumor type and treatment regimen;Onset timing and organ involvement of irAEs;CTCAE grading;Management strategies (e.g., corticosteroids and other immunosuppressive therapies);Time to resolution and recovery patterns;Treatment interruption, discontinuation, or rechallenge;Oncologic outcomes, including response, progression-free survival, and overall survival;A predefined subgroup analysis will include patients who undergo ICI rechallenge after irAE resolution or stabilization.

4. Biospecimen Collection and Translational Analyses When clinically indicated and feasible, biospecimens may be collected during routine clinical care or under additional informed consent. These may include peripheral blood samples and organ-specific specimens associated with irAE presentation.

   Specimen types may include, but are not limited to:Peripheral blood samples;Organ-specific samples obtained during standard diagnostic or therapeutic procedures;Residual clinical specimens obtained as part of routine care;Exploratory analyses may include immune cell profiling, inflammatory mediator assessment, and tissue-level characterization to identify biological features associated with irAE severity, resolution, and recurrence following ICI rechallenge.

   All biospecimen collection and use will comply with institutional ethical approval and informed consent requirements.

5. Clinical Significance This study aims to comprehensively characterize the clinical spectrum of immune-related adverse events (irAEs) occurring during immune checkpoint inhibitor (ICI) therapy in real-world practice. By systematically describing patterns of onset, organ involvement, severity, management strategies, and long-term outcomes, this study will provide a more complete understanding of the natural history and heterogeneity of irAEs.

Through integration of clinical data and exploratory translational analyses, the findings may contribute to improved risk stratification, toxicity monitoring, and individualized management strategies for patients receiving ICIs. In addition, evaluation of ICI rechallenge following irAE resolution will offer supportive evidence for optimizing treatment continuity while maintaining patient safety.

Overall, this study seeks to enhance comprehensive toxicity management across the full course of immunotherapy.

Inclusion Criteria:

• Adults (≥18 years old) with a diagnosis of malignant tumor.
• Received treatment with immune checkpoint inhibitors (including anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 agents).
• Developed documented immune-related adverse events (irAEs) during ICI therapy, as determined by treating physicians.
• Availability of clinical data for evaluation of irAE characteristics and outcomes.

Exclusion Criteria:

• Patients receiving ICIs outside of the participating institution without accessible clinical records.
• Insufficient clinical information to determine irAE diagnosis or outcomes.
• Patients who decline use of their clinical data or biospecimens, when applicable.

Adult cancer patients treated with immune checkpoint inhibitors at Peking Union Medical College Hospital who develop immune-related adverse events during therapy. The study includes patients with various tumor types and organ-specific irAEs. Clinical data, management strategies, outcomes, and rechallenge status will be analyzed. Biospecimens may be collected when clinically indicated and available.

At this time, plans for sharing individual participant data (IPD) have not been finalized. Data sharing may be considered after completion of the primary analyses and subject to institutional review, ethical approval, and data protection requirements.