Data from Association of Tumor Microenvironment T-cell Repertoire and Mutational Load with Clinical Outcome after Sequential Checkpoint Blockade in Melanoma

作者：Erik Yusko, Marissa Vignali, Richard K. Wilson, Elaine R. Mardis, F. Stephen Hodi, Christine E. Horak, Han Chang, David Woods, Harlan Robins, Jeffrey S. Weber · 年份：2023 · DOI：10.1158/2326-6066.c.6549220.v1 · 研究领域：CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

<div>AbstractTo understand prognostic factors for outcome between differentially sequenced nivolumab and ipilimumab in a randomized phase II trial, we measured T-cell infiltration and PD-L1 by IHC, T-cell repertoire metrics, and mutational load within the tumor. We used next-generation sequencing (NGS) and assessed the association of those parameters with response and overall survival. Immunosequencing of the T-cell receptor β-chain locus (TCRβ) from DNA of 91 pretreatment tumor samples and an additional 22 pairs of matched pre- and posttreatment samples from patients who received nivolumab followed by ipilimumab (nivo/ipi), or the reverse (ipi/nivo), was performed to measure T-cell clonality and fraction. Mutational and neoantigen load were also assessed by NGS in 82 of the 91 patients. Tumors were stained using IHC for PD-L1+ and CD8+ T cells. Pretreatment tumor TCR clonality and neoantigen load were marginally associated with best response with nivo/ipi (P = 0.04 and 0.05, respectively), but not with ipi/nivo. Amalgamated pretreatment mutational load and tumor T-cell fraction were significantly associated with best response with nivo/ipi (P = 0.002). Pretreatment PD-L1 staining intensity and CD8+ T-cell counts were correlated with T-cell fraction and clonality, but not mutational or neoantigen load. Patients with increased T-cell fraction posttreatment ...