Immune checkpoint inhibitors (ICIs) have transformed the treatment of solid tumors but are associated with immune-related adverse events (irAEs) that can affect virtually any organ system. While many irAEs are well recognized, neurological, neurocognitive, and psychiatric toxicities remain diagnostically challenging, potentially severe, and poorly understood, with limited predictive biomarkers.
This prospective longitudinal observational cohort study enrolls adult patients with solid tumors initiating a new course of ICI therapy. Participants undergo standardized baseline clinical assessments and biospecimen collection prior to ICI initiation, followed by longitudinal follow-up and event-driven sampling. Patients are dynamically assigned to organ-specific irAE cohorts based on the first clinically significant irAE that dictates management. Patients without grade ≥2 irAEs during follow-up serve as a comparator control cohort.
The primary objective is to characterize longitudinal immune and inflammatory biomarker trajectories associated with the development of irAEs and to identify predictive and prognostic biomarkers, with particular emphasis on neurological, neurocognitive, and psychiatric toxicities. Integrated clinical, imaging, and multi-omics data will be used to elucidate mechanisms of toxicity and inform future risk stratification and personalized management strategies.
Age ≥18 years
Histologically confirmed solid malignancy
Planned initiation of a new immune checkpoint inhibitor regimen (monotherapy or combination) as standard of care or on an approved clinical trial
Ability to provide informed consent
Uncontrolled medical, psychiatric, or social conditions that would interfere with study participation or data interpretation
Chronic systemic immunosuppression exceeding 10 mg/day prednisone equivalent within 14 days prior to enrollment (excluding inhaled, topical, or physiologic replacement doses)
Prior solid organ transplantation or allogeneic hematopoietic stem cell transplantation
Untreated, symptomatic, or progressing brain metastases (treated and stable brain metastases allowed if off systemic steroids for at least 7 days)
Adult patients (≥18 years) with histologically confirmed solid malignancies who are initiating a new immune checkpoint inhibitor regimen, either as standard of care or within an approved clinical trial. Participants are enrolled prior to the first immune checkpoint inhibitor dose and followed longitudinally to assess the development of immune-related adverse events and associated immune and inflammatory biomarker changes.
Cohort
Prospective
Not listed
7
Trial groupsSee each trial group below.
Time to Clinical Resolution of Immune-Related Adverse Events (Days)
Among participants who develop grade ≥2 immune-related adverse events (irAEs), the time from irAE diagnosis and initiation of organ-specific treatment (per institutional guidelines) to achievement of organ-specific clinical resolution will be recorded. Criteria for clinical resolution differ by organ system and are defined according to established consensus guidelines, as specified in the corresponding secondary outcome measures.
Neuro-Sensory irAE Subgroup: Proportion of Participants with Modified Rankin Scale (mRS) Score ≤2
Among participants with immune-mediated neurological events (e.g., encephalitis, myelitis, plexopathy), functional status will be assessed using the Modified Rankin Scale. An mRS score ≤2 (slight disability, able to live independently) is a widely accepted threshold for favorable neurological outcome in neuroimmunology clinical trials.
Neuro-Sensory irAE Subgroup:Proportion of Participants with Objective Improvement on Nerve Conduction Studies
Among participants with immune-mediated peripheral neuropathy, electrophysiologic improvement will be assessed using nerve conduction studies and electromyography. Objective improvement is defined as ≥20% improvement in motor or sensory nerve action potential amplitude or conduction velocity compared with the acute phase, according to EFNS/PNS criteria.
Psychiatric and Cognitive irAE Subgroup:Proportion of Participants with Patient Health Questionnaire-9 (PHQ-9) Score <10
Among participants with immune-mediated major depressive episodes, depressive symptoms will be assessed using the PHQ-9. A score \<10 represents remission or mild symptoms and is an internationally accepted threshold distinguishing clinically significant depression from response/remission.
Psychiatric and Cognitive irAE Subgroup:Proportion of Participants with ≥0.5 Standard Deviation Improvement on ≥2 Standardized Neuropsychological Tests
Among participants with immune-mediated cognitive impairment, standardized neuropsychological test batteries (including the Hopkins Verbal Learning Test-Revised and Trail Making Test Part B) will be administered. Clinically meaningful cognitive improvement is defined as ≥0.5 standard deviation improvement from the acute phase in at least two distinct cognitive domains.
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Shantou University Medical College
Lead sponsor
Fujian Medical University
Collaborator
The First Affiliated Hospital of Zhengzhou University
Collaborator
Sun Yat-sen University
Collaborator
Chinese PLA General Hospital
Collaborator
