Photo Credit: KS Kim
The following is a summary of “Immunogenomic Landscape of Peripheral High-Dose IL-2 Pharmacodynamics in Patients with Metastatic Renal Cell Carcinoma: A Benchmark for Next-Generation IL-2–Based Immunotherapies,” published in the May 2024 issue of Allergy & Immunology by Beebe et al.
High-dose (HD) IL-2 was the pioneering immuno-oncology agent approved for advanced renal cell carcinoma and metastatic melanoma treatment. However, its use was constrained by significant toxicity. To address this, next-generation IL-2 agents are under development to enhance tolerability. Nonetheless, a gap remains in understanding the genomic markers that characterize the target pharmacology for HD IL-2 itself.
For a study, researchers sought to explore the genomic markers associated with HD IL-2 pharmacology through a detailed RNA-sequencing immunogenomic survey of peripheral blood mononuclear cells (PBMCs) collected from patients undergoing HD IL-2 treatment.
They conducted a retrospective observational study, analyzing PBMC samples from 23 patients with metastatic renal cell carcinoma treated with HD IL-2 between 2009 and 2015. The study extended previous findings from flow cytometry analyses by incorporating RNA-sequencing data. They examined bulk PBMC samples collected immediately before (day 1), during (day 3), and after (day 5) treatment in cycle 1 and/or cycle 2 of the initial HD IL-2 course. The analysis focused on gene expression changes and immune gene signatures associated with HD IL-2 treatment.
By day 3, a majority of lymphoid cell types showed a transient decrease, while myeloid transcripts exhibited an increase. Although most genes and/or signatures generally reverted to baseline levels by day 5, certain genes indicative of B cell, NK cell, and T cell proliferation and effector functions continued to rise. Additionally, B cell oligoclonal expansion persisted, unlike T cell expansion. Regulatory T cells progressively expanded during and after treatment, showing a strong negative correlation with myeloid effector cells.
The comprehensive RNA-sequencing immunogenomic survey of HD IL-2 pharmacology provides a valuable pharmacological context, complementing previous flow cytometry results. The findings offered important insights into PBMC gene expression changes associated with IL-2 treatment and informed the development of IL–2–related compounds currently in the pipeline.
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