Tumor microenvironment T-cell repertoire and mutational load are independently associated with the outcome of sequential checkpoint inhibition in melanoma
Yusko E1, Vignali M1, Wilson R2**, Mardis E2**, Hodi S3, Horak, C4, Chang, H4 Woods, D.M5, Robins, H1,6, and Weber J.5*
Adaptive Biotechnologies, Seattle, WA1; McDonnell Genome Institute, Washington University in Saint Louis, St Louis, MO2; Dana Farber Cancer Center, Boston, MA3, Bristol Myers Squibb, Princeton, NJ4, and Laura and Isaac Perlmutter Cancer Center/NYU -Langone Medical Center, New York, NY5, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA6
Purpose: To understand differences in outcome between differentially sequenced nivolumab and ipilimumab, we measured PD-L1 staining, T-cell repertoire metrics, and mutational load within the tumor.
Methods: DNA from 91 pre-treatment tumor samples derived from a randomized trial of nivolumab followed by ipilimumab (nivo/IPI), or the reverse (IPI/nivo) was assessed by immunosequencing of the T-cell receptor beta chain locus (TCRb) to measure tumor T-cell clonality and T-cell fraction including 22 pairs of matched pre- and post-treatment samples and for mutational and neo-antigen load in 82 samples. Seventy flow-sorted pre-treatment peripheral blood T-cell samples were also subjected to TCRb immunosequencing. Tumors were stained using immunohistochemistry for PD-L1 and CD8+ T cells. Results: Tumor TCR clonality was associated with best response with nivo/IPI (p = 0.04), but not IPI/nivo. Mutational and neo-antigen load were associated with best response for nivo/IPI (p = 0.06/0.05 respectively), but not IPI/nivo. Amalgamated mutational load and tumor T-cell fraction was associated with best response with nivo/IPI (p = 0.002). Patients with increased T-cell fraction at week 13 had a 30-fold increased likelihood of survival (p = 0.002). PD-L1 staining intensity and CD8+ T cell counts were correlated with T-cell fraction and clonality, but not mutational or neoantigen load.
Conclusion: Mutational and neo-antigen load, TCR Clonality, and T-cell infiltrate within the tumor were associated with outcome with sequential checkpoint inhibition using nivolumab then ipilimumab, but not when ipilimumab was administered before nivolumab.
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