McFaline-Figueroa J Ricardo, Sun Lu, Youssef Gilbert C, Huang Raymond, Li Gang, Kim Jiyoon, Lee Eudocia Q, Nayak Lakshmi, Chukwueke Ugonma, Beroukhim Rameen, Batchelor Tracy T, Chiocca E Antonio, Everson Richard G, Doherty Lisa, Stefanik Jennifer, Partridge Kathryn, Spearman Amanda, Myers Alexa, Westergaard Catharina, Russ Alyssa, Lavallee Maria, Smokovich Anna, LaForest-Roys Corey, Garcia Fox Rachel, McCluskey Christine, Bi Wenya Linda, Arnaout Omar, Peruzzi PierPaolo, Cosgrove G Rees, Ligon Keith L, Arrillaga-Romany Isabel, Clarke Jennifer L, Reardon David A, Cloughesy Timothy F, Prins Robert M, Wen Patrick Y
Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Brain & Spine Tumor Center, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Nat Commun. 2024 Dec 30;15(1):10757. doi: 10.1038/s41467-024-54326-7.
Glioblastoma is immunologically "cold" and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655). Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma and our secondary endpoint of PFS-6 was 19.5% (95% CI: 9.29-41.2%) for the pooled neoadjuvant cohorts. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.
胶质母细胞瘤在免疫方面呈“冷”态，对单药免疫检查点抑制剂（ICI）耐药。我们之前关于新辅助帕博利珠单抗治疗可手术切除的复发性胶质母细胞瘤的研究确定了对ICI反应的分子特征，并表明新辅助帕博利珠单抗可能改善生存。为了增强这一观察结果的说服力，我们额外招募了25名患者，以评估与新辅助帕博利珠单抗相关的细胞周期基因特征作为主要终点，并对切除的肿瘤组织进行了批量RNA测序（NCT02852655）。新辅助帕博利珠单抗与细胞周期/癌症增殖基因的抑制以及T细胞/干扰素相关基因表达的上调有关。该特征是接受新辅助帕博利珠单抗治疗患者所特有的，并且是生存的独立阳性风险因素。我们的结果证明了抗PD1治疗在胶质母细胞瘤中具有明确的药效学作用，并确定了可能介导耐药的途径。然而，我们并未证实在复发性胶质母细胞瘤中使用新辅助帕博利珠单抗能带来生存获益，并且对于汇总的新辅助队列，我们的无进展生存期6个月的次要终点为19.5%（95%置信区间：9.29 - 41.2%）。我们的新数据表明，一些患者可能对术前ICI表现出先天性耐药，需要其他联合疗法来有效致敏。
