Despite potential life-changing morbidity or even mortality, there are no validated biomarkers for identifying patients at risk of developing serious immune-related adverse events (irAE) from immune checkpoint inhibitor (ICI) therapy. Autoimmune conditions and irAE both involve loss of tolerance to endogenous antigens with similar clinical manifestation. We have previously shown that individuals with irAE have higher baseline IgG autoantibody (autoAb) levels with a greater increase in IgG and IgM autoAb after ICI administration, compared to those without irAE. Previous studies have identified associations and potential mechanistic relationships between the gut microbiome and development of irAE. We hypothesize that changes in gut microbiome, autoAb profiles, and peripheral immunophenotype with ICI therapy are associated with the development of irAE and are influenced by immunosuppressive treatment for irAE.
INSPECT-IO is a prospective Princess Margaret Cancer Centre initiative that aims to identify correlates of irAE in adults (>18 years) with advanced solid tumors [NCT04107311]. Patients receiving ICI-based combination immunotherapy are included given their higher risk of irAE compared to those on ICI monotherapy. Those with a history of autoimmune disease and a flare episode within one year are excluded. Whole blood and stool samples are collected from all patients at baseline (≤ 28 days prior to ICI), at an early timepoint (2 – 6 weeks after starting ICI) and end of treatment (≤ 28 days after completion of ICI). Additional blood and stool samples are collected within 96 hours of onset, and upon resolution of every significant irAE (≥ grade 2 by CTCAE v5.0 or requiring systemic immunosuppression). Shotgun sequencing will be used to determine gut microbial taxonomic and metagenomic composition; autoAb profiling will be performed by multiplex proteomic arrays and immunophenotyping will be done using flow cytometry. Archival tumor tissue and organ-specific tissue biopsies for histologic irAE diagnosis will be stored for additional molecular analyses. Study enrolment is ongoing (37 patients to date) with a target accrual of 120 patients.
NCT04107311.
University Health Network.
GSK.
A.R. Abdul Razak: Non-Financial Interests, Personal, Advisory Role: Adaptimmune, Bayer, GlaxoSmithKline; Non-Financial Interests, Institutional, Research Grant: Deciphera, Karyopharm Therapeutics, Pfizer, Roche/Genentech, Bristol Myers Squibb, MedImmune, Amgen, Blueprint Medicines, Merck, AbbVie, Interion Therapeutics, 23 and me, Rain Therapeutics, Neoleukin, Daiichi Dankyo, Symphogen; Non-Financial Interests, Personal and Institutional, Research Grant: GlaxoSmithKline, Adaptimmune; Non-Financial Interests, Personal, Expert Testimony: Medison. P.L. Bedard: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Sanofi, Merck, Pfizer, Zymeworks, Nektar Therapeutics, Lilly, SeaGen; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Servier; Non-Financial Interests, Personal, Invited Speaker, Executive Board Member: Breast International Group; Non-Financial Interests, Personal, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Personal, Leadership Role, Past Chair IND Committee Member, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Personal, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead. L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Oncorus, Seattle Genetics, Voronoi, Arvinas, Tessa, Navire, Relay Therapeutics, Janpix, Amgen, Marengo, InterRNA, Medicenna, Hoopika, Coherus; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Invited Speaker: Novartis, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Astellas, Bayer, Amgen, Symphogen, Intensity Therapeutics, Shattucks, EMD Serono; Non-Financial Interests, Personal, Advisory Role: ICR. B. Coburn: Non-Financial Interests, Personal and Institutional, Other, In Kind: Nubiyota. A. Spreafico: Financial Interests, Personal, Advisory Board: Merck, Bristol Myers Squibb, Novartis, Oncorus, Janssen, Medison & Immunocore; Financial Interests, Institutional, Research Grant: Novartis, Bristol Myers Squibb, Symphogen, AstraZeneca/MedImmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma/Pfizer, GlaxoSmithKline, Treadwell, Amgen. All other authors have declared no conflicts of interest.