Mastrolonardo Eric V, Nunes Kathryn L, Llerena Pablo, Nikitina Anastasia, Sobol Anastasia, Scott E Reilly, Tuluc Madalina, Davitt Christopher J H, Scher Jessica, Tekumalla Sruti, Mann Derek, Henao Camilo, Jegede Victor, Gargano Stacey, Harshyne Larry A, Alnemri Angela, Tyshevich Andrey, Kushnarev Vladimir, Chasse Madison, Sookiasian Danielle, Axelrod Rita, Zhan Tingting, Leiby Benjamin E, Old Matthew, Seim Nolan, Mahoney My G, Martinez-Outschoorn Ubaldo, Cognetti David M, Curry Joseph M, Prendergast George, Argiris Athanassios, South Andrew P, Linnenbach Alban J, Johnson Jennifer M, Luginbuhl Adam J
Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
BostonGene, Corp., Waltham, Massachusetts.
Clin Cancer Res. 2025 Feb 3;31(3):515-528. doi: 10.1158/1078-0432.CCR-24-0037.
We evaluated whether indoleamine 2,3-dioxygenase (IDO1) inhibitor (IDOi) BMS986205 + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable head and neck squamous cell carcinoma (HNSCC). We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response.
Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 orally daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by human papillomavirus (HPV) status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after treatment with nivolumab in both arms. Nonresponders underwent surgical resection, whereas responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing.
Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (P = 0.909). Treatment was well tolerated, with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDOi augmented rates of pTR in patients with high baseline IDO1 RNA expression (P < 0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus nonresponders (P = 0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-γ expression in the HPV- cohort correlated with response. The HPV+ cohort found B-cell and cancer-associated fibroblast signatures predictive of response/nonresponse.
Response-adaptive surgical timing enhanced treatment response. IDOi BMS986205 augmented pTR in patients with high IDO1 expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.
我们评估了吲哚胺2,3-双加氧酶（IDO1）抑制剂（IDOi）BMS986205联合程序性死亡受体1（PD-1）抑制剂纳武单抗是否能增强未接受过治疗的可切除头颈部鳞状细胞癌（HNSCC）患者的T细胞活性并增强免疫介导的抗肿瘤反应。我们采用适应性反应手术时机来识别免疫治疗的反应者并增强其反应。
HNSCC患者按3:1随机分组，分别每日口服纳武单抗联合或不联合BMS986205（NCT03854032）。在联合治疗组中，BMS986205在纳武单抗前7天开始使用。患者按人乳头瘤病毒（HPV）状态分层。适应性反应手术时机包括在两组接受纳武单抗治疗4周后通过影像学标准进行反应评估。无反应者接受手术切除，而有反应者在手术前再接受4周的随机治疗。生物标志物分析采用病理治疗反应（pTR）和RNA测序。
共纳入42例患者，纳武单抗联合IDOi并未导致更高的影像学反应率（P = 0.909）。治疗耐受性良好，仅有2例（5%）患者出现3级免疫相关不良事件。在基线IDO1 RNA表达高的患者中，添加IDOi可提高pTR率（P < 0.05）。适应性反应手术时机在区分病理反应者与无反应者方面显示出可靠性（P = 0.009）。HPV阴性队列中的预处理自然杀伤细胞特征、PD-L1状态和干扰素-γ表达与反应相关。HPV阳性队列发现B细胞和癌症相关成纤维细胞特征可预测反应/无反应。
适应性反应手术时机增强了治疗反应。IDOi BMS986205提高了基线样本中IDO1表达高的患者的pTR，表明需要识别并靶向免疫治疗耐药节点。HPV状态依赖性特征预测HNSCC对免疫治疗的反应值得进一步研究。
