IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma

被引:52
作者
Reijers, Irene L. M. [1 ]
Rao, Disha [2 ]
Versluis, Judith M. [1 ]
Menzies, Alexander M. [3 ,4 ,5 ,6 ]
Dimitriadis, Petros [2 ]
Wouters, Michel W. [7 ,8 ]
Spillane, Andrew J. [3 ,4 ,9 ,10 ]
Klop, Willem M. C. [11 ]
Broeks, Annegien [12 ]
Bosch, Linda J. W.
Lopez-Yurda, Marta [13 ]
van Houdt, Winan J. [7 ]
Rawson, Robert V. [3 ,4 ,14 ,15 ,16 ]
Grijpink-Ongering, Lindsay G. [13 ]
Gonzalez, Maria [3 ]
Cornelissen, Sten [12 ]
Bouwman, Jasper
Sanders, Joyce [12 ]
Plasmeijer, Elsemieke [17 ,18 ]
Elshot, Yannick S. [17 ,19 ]
Scolyer, Richard A. [3 ,4 ,14 ,15 ,16 ,20 ]
van de Wiel, Bart A. [21 ]
Peeper, Daniel S. [2 ]
van Akkooi, Alexander C. J. [3 ,4 ,22 ]
Long, Georgina V. [3 ,4 ,5 ,6 ,20 ]
Blank, Christian U. [1 ,2 ,23 ]
机构
[1] Netherlands Canc Inst, Dept Med Oncol, Amsterdam, Netherlands
[2] Netherlands Canc Inst, Mol Oncol & Immunol, Amsterdam, Netherlands
[3] Univ Sydney, Melanoma Inst Australia, Sydney, Australia
[4] Univ Sydney, Fac Med & Hlth, Sydney, Australia
[5] Royal North Shore Hosp, Dept Med Oncol, Sydney, Australia
[6] Mater Hosp, Dept Med Oncol, Sydney, Australia
[7] Netherlands Canc Inst, Dept Surg Oncol, Amsterdam, Netherlands
[8] Leiden Univ Med Ctr, Dept Biomed Data Sci, Leiden, Netherlands
[9] Royal North Shore Hosp, Dept Breast & Melanoma Surg, Sydney, Australia
[10] Mater Hosp, Dept Breast & Melanoma Surg, Sydney, Australia
[11] Netherlands Canc Inst, Dept Head & Neck Surg Oncol, Amsterdam, Netherlands
[12] Netherlands Canc Inst, Core Facil & Mol Pathol & Biobanking Dept, Amsterdam, Netherlands
[13] Netherlands Canc Inst, Biometr Dept, Amsterdam, Netherlands
[14] Royal Prince Alfred Hosp, Dept Tissue Pathol, Sydney, Australia
[15] Royal Prince Alfred Hosp, Dept Diagnost Oncol, Sydney, Australia
[16] NSW Hlth Pathol, Sydney, Australia
[17] Netherlands Canc Inst, Dept Dermatol, Amsterdam, Netherlands
[18] Leiden Univ Med Ctr, Dept Dermatol, Leiden, Netherlands
[19] Univ Amsterdam, Dept Dermatol, Amsterdam UMC, Amsterdam, Netherlands
[20] Univ Sydney, Charles Perkins Ctr, Sydney, Australia
[21] Netherlands Canc Inst, Dept Pathol, Amsterdam, Netherlands
[22] Royal Prince Alfred Hosp, Dept Melanoma Surg Oncol, Sydney, Australia
[23] Leiden Univ Med Ctr, Dept Internal Med, Leiden, Netherlands
基金
英国医学研究理事会;
关键词
PATHOLOGICAL RESPONSE; NIVOLUMAB; IMMUNOTHERAPY; RELATLIMAB; SURVIVAL; IMMUNITY; TRIAL;
D O I
10.1084/jem.20221952
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
In the DONIMI trial, a baseline IFN-gamma signature enables prospective selection of patients who can benefit from anti-PD-1 monotherapy. In contrast to results of our murine melanoma model, domatinostat (a class I HDAC inhibitor) does not add benefit to neoadjuvant anti-PD-1 +/- anti-CTLA-4 in patients. Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-gamma (IFN-gamma) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-gamma response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-gamma high and low cohorts, we developed a baseline IFN-gamma signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-gamma scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-gamma scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab +/- ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-gamma score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.
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页数:21
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