Immunomodulatory effects of the ATR inhibitor ceralasertib in a window of opportunity biomarker trial in patients with head and neck squamous cell carcinoma

CANCER RESEARCH(2023)

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摘要
Abstract Head and neck squamous cell carcinoma (HNSCC) is frequently locally advanced, but has a high risk of recurrence after initial treatment. Immune checkpoint blockade with PD-1/PD-L1 inhibitors has revolutionized treatment in the recurrent setting, but resistance to these therapies frequently occurs. Combination of checkpoint inhibitors with the ATR inhibitor ceralasertib could provide an exciting opportunity, with encouraging clinical activity reported in melanoma and non-small cell lung cancer (Kwon et al. 2022; Kim et al. 2022; Besse et al. OA15.05 IASLC 2022 WCLC). This phase 1b trial provided a unique opportunity to understand the immunomodulatory impact of DNA Damage Response (DDR) inhibitors in a clinical setting. NCT03022409 is an open-label, randomized window of opportunity trial where patients with HNSCC were treated with either the PARP inhibitor olaparib (300mg BID) or ceralasertib (160mg BID) for 9-21 days, prior to definitive surgery (or on-treatment biopsy). 21 patients were randomized; n=12 to ceralasertib and n=9 to olaparib, and ceralasertib data will be presented here. Translational endpoints on frozen and fixed tumor biopsies included spatial pharmacokinetics, pharmacodynamic biomarkers, multiplexed fluorescence of tumor infiltrating immune cells and gene expression panels. Blood assessments included cytokine detection, immune cell phenotyping and gene expression. Primary endpoint analysis utilized a bespoke prognostic immune-focused gene signature and secondary endpoint an IHC immunoscore, both aimed to measure if tumors would shift from a ‘cold’ to ‘hot/active’ immune state. We observed an ‘on-drug’ selective suppression of proliferating Ki67+ T-cells (but not total T-cells) in the tumor microenvironment and periphery, followed by a repopulation and median rebound of 63.8% and 187.5% above baseline levels for peripheral helper (CD4+Ki67+; n=8) and cytotoxic (CD8+Ki67+; n=7) T-cells respectively, when ceralasertib dose stopped. IL-12 plasma cytokine levels dropped on ceralasertib treatment and returned to baseline levels ‘off-drug’ in 8/10 patients. Type-I interferon (IFN1) gene expression associated signatures were also upregulated in PBMCs, suggestive of an immune priming effect. 0/2 and 2/4 patients on ceralasertib met their primary and secondary endpoints respectively, however, interpretation is limited due to small numbers of evaluable patients. 1 patient had a grade 3 serious adverse event of chest pain in the ceralasertib arm. There were no unexpected safety findings for either drug and adverse events were generally low grade. The translational data has generated new insights into the immunomodulatory effect of ceralasertib. Further evaluation of the combination of ceralasertib with immune checkpoint blockade is warranted to explore this novel immune mechanism of action. Citation Format: Gemma N. Jones, Sonia Iyer, Marta Milo, Pei-Jen Lou, Melonie A. Nance, Carlos A. Gomez-Roca, Nathan Standifer, Paola Marco-Casanova, Shaan Gill, Michael Surace, Richard Bystry, Maria Alexandrova, Sophie Willis, Jaime Rodriguez-Canales, Andreas Dannhorn, Bienvenu Loembé, Alan Lau, Natalia Lukashchuk, Elizabeth A. Harrington, Elhan Sanai, Emma Dean, Umamaheswar Duvvuri. Immunomodulatory effects of the ATR inhibitor ceralasertib in a window of opportunity biomarker trial in patients with head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT198.
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atr inhibitor ceralasertib,squamous cell carcinoma,opportunity biomarker trial
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