Predicting recurrent glioblastoma clinical outcome to immune checkpoint inhibition and low-dose bevacizumab with tumor in situ fluid circulating tumor DNA analysis.

IF 4.6 2区 医学 Q2 IMMUNOLOGY Cancer Immunology, Immunotherapy Pub Date : 2024-08-06 DOI:10.1007/s00262-024-03774-7
Guangzhong Guo, Ziyue Zhang, Jiubing Zhang, Dayang Wang, Sensen Xu, Guanzheng Liu, Yushuai Gao, Jie Mei, Zhaoyue Yan, Ruijiao Zhao, Meiyun Wang, Tianxiao Li, Xingyao Bu
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Abstract

Objective: Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy.

Methods: In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment.

Results: The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis.

Conclusions: Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment.

Clinical trial registration: This trial is registered with ClinicalTrials.gov, NCT05540275.

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利用肿瘤原位液循环肿瘤DNA分析预测免疫检查点抑制剂和小剂量贝伐单抗对复发性胶质母细胞瘤的临床疗效
目的:大多数复发性胶质母细胞瘤(rGBM)患者不能从免疫检查点抑制剂中获益,这就强调了反应生物标志物的必要性。本研究评估了肿瘤原位液(TISF)循环肿瘤DNA(ctDNA)是否可作为rGBM患者对小剂量贝伐单抗(Bev)加抗PD-1疗法反应的生物标志物,旨在增强免疫疗法的全身反应:在这项II期试验中,32名经标准治疗后首次复发的GBM患者入组,然后每个周期接受替赛珠单抗加小剂量贝伐单抗治疗。每次治疗前,使用 551 个基因面板对 TISF 样本进行 ctDNA 分析:中位无进展生存期(mPFS)和总生存期(mOS)分别为8.2个月(95% CI,5.2-11.1)和14.3个月(95% CI,6.5-22.1)。12个月的OS为43.8%,客观反应率为56.3%。与基线TISF-ctDNA相比,治疗后突变等位基因比例和肿瘤突变负荷减少20%以上的患者预后明显较好。在可检测到的基因突变中,MUC16突变、表皮生长因子受体(EGFR)突变和扩增、SRSF2扩增和H3F3B扩增的患者与较差的预后明显相关:小剂量Bev加抗PD-1治疗可明显改善rGBM患者的OS,对未来的个体化治疗策略具有指导意义。TISF-ctDNA可以监测rGBM患者对联合治疗的反应,指导治疗:本试验已在 ClinicalTrials.gov 登记,编号为 NCT05540275。
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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
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