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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.

Author information

1
Adaptive Biotechnologies, Seattle, Washington.
2
McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri.
3
Dana-Farber Cancer Center, Boston, Massachusetts.
4
Bristol-Myers Squibb, Princeton, New Jersey.
5
Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York.
6
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
7
Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York. Jeffrey.weber2@nyumc.org.

Abstract

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.

PMID:
30635271
PMCID:
PMC6397694
[Available on 2020-03-01]
DOI:
10.1158/2326-6066.CIR-18-0226

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