Longitudinal Cohort Study of Immune-Related Adverse Events in Solid Tumor Patients Treated With Immune Checkpoint Inhibitors

Longitudinal Cohort Study of Immune-Related Adverse Events in Solid Tumor Patients Receiving Immune Checkpoint Inhibitors, With Deep Phenotyping and Multi-Omics Biomarker Discovery

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.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor; Immune-Related Adverse Events; Immunotherapy Toxicity

Detailed Description

Immune checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 pathways have demonstrated substantial clinical benefit across multiple solid malignancies. However, their mechanism of action can also lead to immune-related adverse events (irAEs), which may involve dermatologic, gastrointestinal, hepatic, pulmonary, endocrine, musculoskeletal, cardiovascular, renal, hematologic, neurological, and psychiatric systems. Neurological and neurocognitive irAEs, in particular, are uncommon but potentially devastating and remain poorly characterized.

This study is a hybrid prospective longitudinal observational cohort designed to move beyond reactive identification of irAEs toward proactive prediction and mechanistic understanding. Adult patients with solid tumors initiating a new ICI regimen are enrolled prior to treatment initiation. Longitudinal clinical data, imaging, and biospecimens are collected at predefined intervals and at the time of suspected irAE onset when feasible.

Participants are assigned to event-defined cohorts based on the first grade ≥2 irAE that drives clinical management, including neuro-sensory, gastrointestinal/hepatic, rheumatologic/musculoskeletal, vascular/renal, hematologic, multi-organ, or control (no significant irAE) cohorts. Deep phenotyping and multi-omics analyses-including immune cell profiling, proteomics, metabolomics, and microbiome analyses-are performed to identify biomarkers associated with irAE risk, severity, and outcomes.

• Study Type: Observational
• Enrollment (Estimated): 940

Contacts and Locations

• Study Contact: Name: Yifei Ma, MD; Phone Number: 8618883852716; Email: myf61872169@163.com

Study Locations

• China
  • Guangzhou, China
    • Recruiting
    • Sun Yat-sen University Cancer Center
    • Contact: Ao Zhang, MD; Phone Number: 8618588811852; Email: zhangao@sysucc.org.cn
    • Principal Investigator: Ao Zhang, MD
  • Sanya, China
    • Recruiting
    • Hainan Hospital of Chinese PLA General Hospital
    • Contact: Jiacai Lin, MD; Phone Number: 8615692537693; Email: sovereignljc@126.com
    • Principal Investigator: Jiacai Lin, MD
  • Shantou, China
    • Recruiting
    • the First Affiliated Hospital of Shantou University Medical College
    • Contact: Jun Lu, MD; Phone Number: 8613531263375; Email: jlu1@stu.edu.cn
    • Principal Investigator: Jun Lu, MD
  • Shantou, China
    • Recruiting
    • Affiliated Cancer Hospital of Shantou University Medical College
    • Contact: Xinjia Wang, MD; Phone Number: 8613881841142; Email: liuhaizhou@fjmu.edu.cn
    • Principal Investigator: Xinjia Wang, MD
  • Zhengzhou, China
    • Recruiting
    • The First Affiliated Hospital of Zhengzhou University
    • Contact: Pengfei Zhu, MD; Phone Number: 8613526664537; Email: tesolik_trevolso@tom.com
    • Principal Investigator: Pengfei Zhu, MD
  • Fujian
    • Fuzhou, Fujian, China, 430074
      • Recruiting
      • First Affiliated Hospital of Fujian Medical University
      • Contact: Yifei Ma, MD; Phone Number: 8618883852716; Email: myf61872169@163.com
      • Principal Investigator: Yifei Ma, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

Inclusion Criteria:

• 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
• Baseline study assessments and biospecimen collection completed prior to first ICI dose
• Life expectancy of at least 6 months as determined by treating oncologist
• Availability of archival tumor tissue or willingness to undergo biopsy if archival tissue is unavailable

Exclusion Criteria:

• 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)
• Inability or unwillingness to provide required baseline biospecimens

Study Plan

How is the study designed?

Number of groups / cohorts

7

Cohorts and Interventions

Group / Cohort
Neuro-Sensory irAE Cohort; Participants who develop a grade ≥2 neurological, neurocognitive, psychiatric, ocular inflammatory, or peripheral nervous system immune-related adverse event.
Gastrointestinal and Hepatic irAE Cohort; Participants who develop grade ≥2 immune-mediated colitis, hepatitis, pancreatitis, or related gastrointestinal toxicities.
Rheumatology and Musculoskeletal irAE Cohort; Participants who develop grade ≥2 inflammatory arthritis, myositis, polymyalgia rheumatica-like syndromes, or related musculoskeletal toxicities.
Vascular and Renal irAE Cohort; Participants who develop grade ≥2 myocarditis, vasculitis, nephritis, or other vascular or renal immune-mediated toxicities.
Hematologic irAE Cohort; Participants who develop grade ≥2 immune-mediated cytopenias or other hematologic toxicities.
Multi-Organ irAE Cohort; Participants who develop two or more distinct grade ≥2 immune-related adverse events involving different organ systems.
Control Cohort; Participants who do not develop any grade ≥2 immune-related adverse events during the defined follow-up period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From irAE diagnosis through up to 24 months of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 weeks after irAE diagnosis
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.	12 weeks after irAE diagnosis
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.	8 weeks after initiation of targeted treatment
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.	12 weeks after irAE diagnosis
Gastrointestinal and Hepatic irAE Subgroup: Proportion of Participants with ≤3 Bowel Movements per Day and No Hematochezia	Among participants with immune-mediated colitis, clinical remission will be assessed. ≤3 bowel movements per day without hematochezia is a widely accepted clinical remission criterion in colitis clinical trials.	2 weeks after initiation of immunosuppressive therapy
Gastrointestinal and Hepatic irAE Subgroup: Proportion of Participants with Alanine Aminotransferase (ALT) ≤1.5 × Upper Limit of Normal	Among participants with immune-mediated hepatitis, biochemical remission will be assessed. ALT ≤1.5 × ULN is a commonly accepted biochemical remission criterion in drug-induced liver injury trials.	4 weeks after initiation of immunosuppressive therapy
Rheumatologic and Musculoskeletal irAE Subgroup: Proportion of Participants with Clinical Disease Activity Index (CDAI) ≤10	Among participants with immune-mediated inflammatory arthritis, disease activity will be assessed using the CDAI. A CDAI score ≤10 defines low disease activity and is an established rheumatologic threshold.	12 weeks after initiation of immunosuppressive therapy
Rheumatologic and Musculoskeletal irAE Subgroup: Proportion of Participants with ≥20% Improvement in Manual Muscle Testing (MMT-8) Score	Among participants with immune-mediated myositis, muscle strength will be assessed using the MMT-8 score. A ≥20% improvement from the acute phase is an established clinically meaningful threshold in myositis trials.	12 weeks after irAE diagnosis
Renal irAE Subgroup: Proportion of Participants with Serum Creatinine Recovery to Within 1.3 × Baseline	Among participants with immune-mediated nephritis, renal recovery will be assessed. Serum creatinine recovery to within 1.3 × baseline represents a stringent and clinically meaningful recovery criterion per KDIGO acute kidney injury guidelines.	12 weeks after irAE diagnosis
Hematologic irAE Subgroup: Proportion of Participants with Sustained Hematologic Response (CTCAE v5.0 Grade ≤1 for ≥4 Weeks)	Among participants with immune-mediated cytopenias, hematologic remission is defined as maintenance of CTCAE v5.0 grade ≤1 blood counts (e.g., platelets ≥75 ×10⁹/L, absolute neutrophil count ≥1.5 ×10⁹/L) for at least 4 weeks without ongoing transfusion or growth factor support.	Within 12 weeks after initiation of first-line immunosuppressive therapy
Hematologic irAE Subgroup: Proportion of Participants with Normalized Lactate Dehydrogenase and Stable Hemoglobin	Among participants with immune-mediated hemolytic anemia, hemolysis control is defined as normalization of lactate dehydrogenase with stable hemoglobin levels for ≥7 days without transfusion support.	2 weeks after initiation of treatment
Multi-Organ irAE Subgroup: Proportion of Participants without Any New or Worsening ≥Grade 3 Immune-Related Adverse Events Across Organ Systems	Among participants with multi-organ irAEs, overall toxicity control is defined as absence of any new or worsening grade ≥3 irAE in any organ system following initiation of treatment.	Within 4 weeks after initiation of combined immunosuppressive therapy
Multi-Organ irAE Subgroup: Proportion of Participants Requiring Intensive Care Unit Admission for Multi-Organ irAE	The proportion of participants requiring intensive care unit admission due to the severity of multi-organ immune-related adverse events will be recorded as an objective marker of disease severity.	irAE diagnosis through resolution or up to 24 weeks
Control Cohort (No Grade ≥2 irAE): Duration of Immunotherapy without Grade ≥2 Immune-Related Adverse Events (Months)	Among participants who do not develop grade ≥2 irAEs, treatment tolerability will be assessed as the time from ICI initiation to first occurrence of grade ≥2 irAE, disease progression, death, or treatment discontinuation.	From ICI initiation through 90 days after last dose
Control Cohort (No Grade ≥2 irAE): Proportion of Participants Completing Planned Immune Checkpoint Inhibitor Course per Protocol	Among participants without grade ≥2 irAEs, the proportion completing the planned ICI treatment course as scheduled will be recorded as a complementary measure of treatment tolerability.	From ICI initiation through 90 days after last dose

Collaborators and Investigators

• Sponsor: Shantou University Medical College
• Collaborators: Sun Yat-sen University; Chinese PLA General Hospital; Fujian Medical University; The First Affiliated Hospital of Zhengzhou University

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2019
• Primary Completion (Estimated): September 10, 2029
• Study Completion (Estimated): September 10, 2029

Study Registration Dates

• First Submitted: December 16, 2025
• First Submitted That Met QC Criteria: January 20, 2026
• First Posted (Actual): January 22, 2026

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 26, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; Biomarkers; Immune checkpoint inhibitors; Neurotoxicity; immune related adverse events; Neuroimmune adverse events; PD-1 blocker
• Additional Relevant MeSH Terms: Nervous System Diseases; Chemically-Induced Disorders; Poisoning; Neurotoxicity Syndromes
• Other Study ID Numbers: 2023100

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Baseline Characteristics & Demographics: Age, sex, race/ethnicity, baseline body weight and height, diagnosis, treatment history, relevant comorbidities, smoking/alcohol status.; Exposure/Treatment Data: Specific checkpoint inhibitor(s) received, dosing regimen, treatment start and end dates, medications.; Laboratory & Diagnostic Data: Serial laboratory test results, key imaging findings relevant to irAEs, pathology reports.; Outcomes: CTCAE grades, date to primary outcomes, management strategies.; Oncologic Outcomes: Tumor response assessments.; Supporting Documents for Data Interpretation.
• IPD Sharing Time Frame: 2026.3 to 2029.1

IPD Sharing Access Criteria

The de-identified IPD and supporting documents will be made available to qualified researchers worldwide upon request. Researchers will have access to the fully de-identified individual participant data listed in the previous section, along with the supporting documents including: the final study protocol, statistical analysis plan, the annotated case report forms. The data dictionary.

All data will be anonymized in accordance with the HIPAA Safe Harbor method. Interested researchers must submit a formal research proposal outlining their study objectives, analysis plan, and ethical considerations via email for review by our Data Access Committee. Requestors will be required to sign a Data Use Agreement that legally binds them to use the data only for the approved purpose, maintain data security, and prevent re-identification or redistribution. Data will then be securely transferred via encrypted file sharing or made available through a controlled-access repository

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No