A single dose of neoadjuvant pd-1 blockade predicts clinical outcomes in resectable melanoma nature medicine grade 9 static electricity test

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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 gas after eating eggs in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 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 electricity cost per kwh by country 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 pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients electricity 2pm live 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.

A.C.H., T.C.M., and E.J.W. conceived and designed the overall studies. A.C.H. and T.C.M. designed the clinical trial at Penn. A.C.H., T.C.M., R.J.O., X.X., M.D.F., and G.C.K. implemented the clinical trial at Penn, and T.C.M. was principal investigator of this clinical trial. X.X. and S.L. performed pathologic response and TIL assessments. A.C.H., R.J.O., P.K.Y., S.M.G., B.B., and R.S.H. performed immune assessment assays. A.C.H., R.J.O., P.K.Y., S.M.G., and M.W.K. analyzed immune assessment data. R.Mick performed biostatistical o gastronomo buffet analyses. S.Manne, Q.Z., W.M.B., R.Mogg, and J.H.Y. performed NanoString assay and/or computational analysis of NanoString data. A.A.K., L.D., B.M.W., B.W., K.D’A., and K.L.N. performed mutational analysis and neoepitope prediction. W.X., L.G., M.C., S.McGettigan, and K.K. assisted in the Penn clinical trial. A.K. and M.D.F. performed radiographic assessments. L.A. and J.H.Y. performed and/or analyzed immunohistochemistry and immunofluorescent assays. G.P.L., R.K.A., G.C.K., M.D.F., and L.M.S. were investigators on the trial. A.C.H., T.C.M., and E.J.W. interpreted the data. A.C.H., T.C.M., and E.J.W. wrote the gas stoichiometry practice manuscript. E.J.W. and T.C.M. designed, interpreted, and oversaw the study. Competing interests

Merck provided funding and drugs for the clinical trial. Merck performed immunohistochemistry, immunofluorescence, and NanoString assays, and played a role in the analysis of these data. Merck played no role in the design wd gaster theme, data collection, decision to publish, or preparation of the manuscript. R.J.O. was at Penn while engaged in this project, but is now currently employed at Merck. L.A., Q.Z., R.M., W.M.B., and J.H.Y. are currently or were employed at Merck when engaged in this project. E.J.W. is a member of the Parker Institute for Cancer Immunotherapy which supported the UPenn cancer immunotherapy program. E.J.W. has consulting agreements with is there a gas station near me and/or is on the scientific advisory board for Merck, Roche, Pieris, Elstar, and Surface Oncology. E.J.W. has a patent licensing agreement on the PD-1 pathway with Roche/Genentech. E.J.W. is a founder of Arsenal Biosciences. T.C.M. has had advisory roles with Bristol-Myers Squibb, Merck, Incyte, Aduro Biotech, and Regeneron. Corresponding authors

a, Changes in tumor PD-L1 pre- versus post-treatment using immunohistochemistry staining ( n = 9 independent paired patient samples). ** P 0.01 using two-sided Wilcoxon matched-pairs test. b, Correlation of percentage of Ki67 + in non-naïve CD8 T cells versus percentage of Ki67 + in Tregs (FoxP3 +CD4) ( n = 21 independent patient samples); R score and P value generated using Pearson’s correlation. c, Thirty-three post-treatment immune static electricity diagram parameters classified by recurrence using random forest analysis and ranked by importance score ( n = 21 independent patient samples). Error bar denotes mean ± s.d. for 1,000 random forest iterations. d, Percentage expression of selected markers in tumor between patients with recurrence (9 independent patient samples) and no recurrence (12 independent patient samples). P value calculated using two-sided gas leak chicago Mann–Whitney test. e, Correlation of percentage of Ki67 + in Tregs (FoxP3 + CD4) versus percentage of Eomes + T-bet – in non-naïve CD8 ( n = 21 independent patient samples); R score and P value generated using Pearson’s correlation. f, Twenty-five pretreatment immune parameters classified by recurrence using electricity voltage in paris random forest analysis and ranked by importance score ( n = 21 independent patient samples). Error bar denotes mean ± s.d. for 1,000 random forest iterations. g, Percentage expression of selected markers in tumor between patients with recurrence (9 independent patient samples) and no recurrence (12 independent patient samples). Two-sided t-test was used for CD45RA -CD27 + and CD45RA +CD27 + comparisons. Two-sided Mann–Whitney test was used for CD8 Ki67 + and CD4 Ki67 + comparisons. Error bar denotes mean ± s.d. h, Scatter plot of percentage of Ki67 + in non-naïve CD8 versus percentage of Ki67 +in FoxP3 + CD4 origin electricity faults (Tregs) at pretreatment stratified by recurrence status. Dotted line denotes non-naïve CD8 Ki67 + of 5.5 calculated by CART analysis as the optimal cut point separating recurrence versus no recurrence ( n = 21 independent patient samples).