OncoMimic peptide-based immunotherapy EO2401 induces shared T cell clusters in patients with adrenal cancer

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BACKGROUND: Patients with advanced malignant adrenal tumors face poor prognoses with limited treatment options. Emerging data suggest that these rare tumors exhibit immunogenicity, potentially benefiting from intensified immunotherapy. METHODS: The SPENCER trial (NCT04187404) evaluates EO2401, an off-the-shelf in vivo peptide immunotherapy containing three synthetic HLA-A*02 restricted-peptides called OncoMimic and derived from human gut commensals that exhibit molecular mimicry to tumor-associated antigens (BIRC5, FOXM1, IL13RA2) combined with nivolumab in patients with locally advanced or metastatic adrenocortical carcinoma (ACC) or malignant pheochromocytoma/ paraganglioma (PPGL). We performed T cell receptor (TCR) repertoire sequencing to profile the TCR architecture in ACC and characterize vaccination imprints. RESULTS: Here we show that ACC patients are characterized by a restricted peripheral T cell richness. EO2401 does not expand highly shared TCR clones across patients but diversifies pre-existing T cell clusters. These clusters are not converging on known neoantigen-specific TCRs but exhibit generation probabilities characteristic of public clones some of which being shared across patients. CONCLUSIONS: These findings suggest that EO2401-based peptide immunotherapy combined with checkpoint inhibition can broaden and activate public, pre-existing T cell clusters, potentially enhancing tumor-specific immune responses.

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