BibTex format
@article{Chan:2025:10.1158/2767-9764.CRC-25-0604,
author = {Chan, Wah Hak C and Patin, EC and Patrikeev, A and Nicastri, A and Kozik, Z and Baldock, H and Kyula-Currie, JN and Roulstone, V and Wongariyapak, A and Gifford, V and Tenev, T and Appleton, ES and Hubbard, LC and Foo, S and Pedersen, M and Choudhary, JS and Ono, M and Melcher, AA and Rullan, A and Harrington, KJ},
doi = {10.1158/2767-9764.CRC-25-0604},
journal = {Cancer Res Commun},
pages = {2079--2091},
title = {Xevinapant plus Chemoradiotherapy Negatively Sculpts the Tumor-Immune Microenvironment in Head and Neck Cancer.},
url = {http://dx.doi.org/10.1158/2767-9764.CRC-25-0604},
volume = {5},
year = {2025}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - UNLABELLED: Xevinapant is an orally bioavailable antagonist of select members of the inhibitor of apoptosis protein family. Despite promising phase II data, combining xevinapant with chemoradiotherapy (CRT) failed to improve outcomes in the phase III TrilynX trial when combined with CRT for locally advanced head and neck squamous cell cancer (SCCHN). In immunocompetent mouse models of SCCHN, xevinapant plus CRT maintained or improved locoregional control but in a CD8+ T cell-independent manner. On addition of xevinapant to CRT, the numbers of tumor-infiltrating cytotoxic CD8+ T cells and NK cells were reduced, with remaining CD8+ T cells characterized by PD-1hi CD38hi expression and Nr4a3 dynamics consistent with nonresponsiveness to antigenic restimulation. Furthermore, combination treatment significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute-phase proteins, and decreased levels of necroptosis mediator receptor-interacting protein kinase 3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumor-immune microenvironment, which may explain its lack of clinical benefit. SIGNIFICANCE: Despite hugely promising randomized phase II study data, combined CRT plus xevinapant failed in the TrilynX phase III clinical trial in locally advanced SCCHN. We show that adding xevinapant to chemoradiotherapy in vivo dysregulates antitumor lymphocyte function, acute-phase proteins, and cell death pathways, with net immunosuppressive effects on the tumor-immune microenvironment.
AU - Chan,Wah Hak C
AU - Patin,EC
AU - Patrikeev,A
AU - Nicastri,A
AU - Kozik,Z
AU - Baldock,H
AU - Kyula-Currie,JN
AU - Roulstone,V
AU - Wongariyapak,A
AU - Gifford,V
AU - Tenev,T
AU - Appleton,ES
AU - Hubbard,LC
AU - Foo,S
AU - Pedersen,M
AU - Choudhary,JS
AU - Ono,M
AU - Melcher,AA
AU - Rullan,A
AU - Harrington,KJ
DO - 10.1158/2767-9764.CRC-25-0604
EP - 2091
PY - 2025///
SP - 2079
TI - Xevinapant plus Chemoradiotherapy Negatively Sculpts the Tumor-Immune Microenvironment in Head and Neck Cancer.
T2 - Cancer Res Commun
UR - http://dx.doi.org/10.1158/2767-9764.CRC-25-0604
UR - https://www.ncbi.nlm.nih.gov/pubmed/41123992
VL - 5
ER -