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Cancer Immunol Res. 2019 Mar;7(3):458-465. doi: 10.1158/2326-6066.CIR-18-0226. Epub 2019 Jan 11.

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

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Adaptive Biotechnologies, Seattle, Washington.
McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri.
Dana-Farber Cancer Center, Boston, Massachusetts.
Bristol-Myers Squibb, Princeton, New Jersey.
Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York.
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York.


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 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 at week 13 had a 30-fold increased likelihood of survival (P = 0.002). 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.

[Available on 2020-03-01]

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