DeMaria Peter Joseph, Bilusic Marijo, Park Deric M, Heery Christopher R, Donahue Renee N, Madan Ravi A, Bagheri Mohammad Hadi, Strauss Julius, Shen Victoria, Marté Jennifer L, Steinberg Seth M, Schlom Jeffrey, Gilbert Mark R, Gulley James L
Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Oncologist. 2021 May;26(5):e847-e858. doi: 10.1002/onco.13720. Epub 2021 Mar 9.
Brachyury is a transcription factor overexpressed in chordoma and is associated with chemotherapy resistance and epithelial-to-mesenchymal transition. GI-6301 is a recombinant, heat-killed Saccharomyces cerevisiae yeast-based vaccine targeting brachyury. A previous phase I trial of GI-6301 demonstrated a signal of clinical activity in chordomas. This trial evaluated synergistic effects of GI-6301 vaccine plus radiation.
Adults with locally advanced, unresectable chordoma were treated on a randomized, placebo-controlled trial. Patients received three doses of GI-6301 (80 × 10 yeast cells) or placebo followed by radiation, followed by continued vaccine or placebo until progression. Primary endpoint was overall response rate, defined as a complete response (CR) or partial response (PR) in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity.
Between May 2015 and September 2019, 24 patients enrolled on the first randomized phase II study in chordoma. There was one PR in each arm; no CRs were observed. Median progressive-free survival for vaccine and placebo arms was 20.6 months (95% confidence interval [CI], 5.7-37.5 months) and 25.9 months (95% CI, 9.2-30.8 months), respectively. Hazard ratio was 1.02 (95% CI, 0.38-2.71). Vaccine was well tolerated with no vaccine-related serious adverse events. Preexisting brachyury-specific T cells were detected in most patients in both arms. Most patients developed T-cell responses during therapy, with no difference between arms in frequency or magnitude of response.
No difference in overall response rate was observed, leading to early discontinuation of this trial due to low conditional power to detect statistical difference at the planned end of accrual.
Chordoma is a rare neoplasm lacking effective systemic therapies for advanced, unresectable disease. Lack of clinically actionable somatic mutations in chordoma makes development of targeted therapy quite challenging. While the combination of yeast-brachyury vaccine (GI-6301) and standard radiation therapy did not demonstrate synergistic antitumor effects, brachyury still remains a good target for developmental therapeutics in chordoma. Patients and their oncologists should consider early referral to centers with expertise in chordoma (or sarcoma) and encourage participation in clinical trials.
短尾蛋白是一种在脊索瘤中过表达的转录因子，与化疗耐药及上皮-间质转化相关。GI-6301是一种以重组热灭活酿酒酵母为基础、靶向短尾蛋白的疫苗。此前一项GI-6301的I期试验显示了在脊索瘤中的临床活性信号。本试验评估了GI-6301疫苗联合放疗的协同效应。
局部晚期、不可切除的脊索瘤成年患者接受一项随机、安慰剂对照试验。患者接受三剂GI-6301（80×10酵母细胞）或安慰剂，随后进行放疗，之后继续使用疫苗或安慰剂直至病情进展。主要终点为总缓解率，定义为24个月时照射肿瘤部位的完全缓解（CR）或部分缓解（PR）。进行免疫分析以评估免疫原性。
2015年5月至2019年9月期间，24例患者参加了脊索瘤的首个随机II期研究。每组各有1例PR；未观察到CR。疫苗组和安慰剂组的中位无进展生存期分别为20.6个月（95%置信区间[CI]，5.7 - 37.5个月）和25.9个月（95%CI，9.2 - 30.8个月）。风险比为1.02（95%CI，0.38 - 2.71）。疫苗耐受性良好，未出现与疫苗相关的严重不良事件。两组大多数患者均检测到预先存在的短尾蛋白特异性T细胞。大多数患者在治疗期间出现T细胞反应，两组反应的频率或强度无差异。
未观察到总缓解率的差异，由于在计划的入组结束时检测统计差异的条件把握度较低，导致该试验提前终止。
脊索瘤是一种罕见肿瘤，对于晚期不可切除疾病缺乏有效的全身治疗方法。脊索瘤缺乏临床上可操作的体细胞突变使得靶向治疗的开发颇具挑战性。虽然酵母短尾蛋白疫苗（GI-6301）与标准放疗联合未显示出协同抗肿瘤作用，但短尾蛋白仍是脊索瘤治疗性药物开发的一个良好靶点。患者及其肿瘤学家应考虑尽早转诊至有脊索瘤（或肉瘤）专业知识的中心，并鼓励参与临床试验。
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