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To 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 immunohistochemistry, 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 post treatment 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 immunohistochemistry 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 = .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 post-treatment at week 13 had a 30-fold increased likelihood of survival (P = .002). Mutational and neoantigen load, and T-cell infiltrate within the tumor, were associated with outcome of sequential checkpoint inhibition using nivolumab then ipilimumab, but not when ipilimumab was administered before nivolumab.
This article was published in the following journal.
Name: Cancer immunology research
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Biochemical identification of mutational changes in a nucleotide sequence.
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