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A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuva...

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Detalles Bibliográficos
Autores principales: Huang, Alexander C., Orlowski, Robert J., Xu, Xiaowei, Mick, Rosemarie, George, Sangeeth M., Yan, Patrick K., Manne, Sasikanth, Kraya, Adam A., Wubbenhorst, Bradley, Dorfman, Liza, D’Andrea, Kurt, Wenz, Brandon M., Liu, Shujing, Chilukuri, Lakshmi, Kozlov, Andrew, Carberry, Mary, Giles, Lydia, Kier, Melanie W., Quagliarello, Felix, McGettigan, Suzanne, Kreider, Kristin, Annamalai, Lakshmanan, Zhao, Qing, Mogg, Robin, Xu, Wei, Blumenschein, Wendy M., Yearley, Jennifer H., Linette, Gerald P., Amaravadi, Ravi K., Schuchter, Lynn M., Herati, Ramin S., Bengsch, Bertram, Nathanson, Katherine L., Farwell, Michael D., Karakousis, Giorgos C., John Wherry, E., Mitchell, Tara C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699626/
https://www.ncbi.nlm.nih.gov/pubmed/30804515
http://dx.doi.org/10.1038/s41591-019-0357-y
Descripción
Sumario:Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8/27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease-free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pre-treatment immune signature (Neoadjuvant Response Signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.