Epigenetic therapy sensitizes anti–PD-1 refractory head and neck cancers to immunotherapy rechallenge
Tingting Qin, … , Maureen A. Sartor, Sara I. Pai
Tingting Qin, … , Maureen A. Sartor, Sara I. Pai
Published March 17, 2025
Citation Information: J Clin Invest. 2025;135(6):e181671. https://doi.org/10.1172/JCI181671.
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Clinical Research and Public Health Immunology Oncology

Epigenetic therapy sensitizes anti–PD-1 refractory head and neck cancers to immunotherapy rechallenge

Abstract

BACKGROUND Immune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, the majority of patients are refractory.METHODS In a nonrandomized, open-label Phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5-azacytidine (5-aza) daily for either 5 or 10 days in combination with durvalumab and tremelimumab after progression on ICB. The primary objective was to assess the biologically effective dose of 5-aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety.RESULTS Thirty-eight percent (3 of 8) of participants with evaluable paired tissue samples had a greater-than 2-fold increase from baseline in IFN-γ signature and CD274 (programmed cell death protein 1 ligand, PD-L1) expression within the tumor microenvironment (TME), which was associated with increased CD8+ T cell infiltration and decreased infiltration of CD4+ T regulatory cells. The mean neutrophil-to-lymphocyte ratio (NLR) decreased by greater than 50%, from 14.2 (SD 22.6) to 6.9 (SD 5.2). Median overall survival (OS) was 16.3 months (95% CI 1.9, NA), 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%), and 58% (7 of 12) of treated participants demonstrated prolonged OS of greater than 12 months.CONCLUSION Our findings suggest that low-dose 5-aza can reprogram systemic host immune responses and the local TME to increase IFN-γ and PD-L1 expression. The increased expression of these established biomarkers correlated with prolonged OS upon ICB rechallenge.TRIAL REGISTRATION ClinicalTrials.gov NCT03019003.FUNDING NIH/NCI P01 CA240239.

Authors

Tingting Qin, Austin K. Mattox, Jean S. Campbell, Jong Chul Park, Kee-Young Shin, Shiting Li, Peter M. Sadow, William C. Faquin, Goran Micevic, Andrew J. Daniels, Robert Haddad, Christopher S. Garris, Mikael J. Pittet, Thorsten R. Mempel, Anne ONeill, Maureen A. Sartor, Sara I. Pai

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Figure 1

Clinical trial schema and multi-omics datasets included in the study.

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Clinical trial schema and multi-omics datasets included in the study. (A...
(A) Participants with locoregional or metastatic head and neck cancer that progressed on prior ICB were enrolled into the clinical trial (www.clinicaltrials.gov; NCT3019003). Participants were treated with escalating doses of a DNA methyltransferase inhibitor, 5-azacytidine (5-aza), and fixed doses of durvalumab (α-PD-L1) and tremelimumab (α-CTLA-4). The primary objective was determining the biologically effective dose (BED) of 5-aza. The secondary outcome was assessing the safety of the combination therapy. (B) Tissue specimens were collected (black arrows) prior to 5-aza treatment (green arrow) and after combination therapy with durvalumab and tremelimumab (purple arrows), which were given at the same time as the second dose of 5-aza (on-treatment).