转移性软组织肉瘤（STS）的全身治疗选择有限，免疫调节尚未显着改善预后。瘤内 (IT) 注射稳定乳剂制剂 (GLA-SE) 中的 Toll 样受体 4 (TLR4) 激动剂吡喃葡萄糖基脂质 A 作为免疫疗法已在其他情况下进行了研究。评估 IT 的安全性、有效性和免疫调节作用GLA-SE 与同步放疗治疗具有可注射病灶的转移性 STS 患者。这项针对 STS 患者的 1 期非随机对照试验于 2014 年 11 月 17 日至 2016 年 3 月 16 日在单一学术肉瘤专业中心进行。进行了数据分析2016 年 8 月至 2022 年 9 月。测试了两种剂量的 IT GLA-SE（5 μg 和 10 μg，共 8 周剂量）与注射病灶同步放疗相结合的安全性。主要终点是安全性和耐受性。次要和探索性终点包括局部缓解率以及通过肿瘤浸润和循环淋巴细胞的免疫组织化学和 T 细胞受体 (TCR) 测序来测量抗肿瘤免疫力。 12 名患者（中位[范围]年龄，65 [34-78]）岁；8 [67%] 女性）在 2 个剂量组中接受治疗。瘤内注射 GLA-SE 耐受性良好，只有 1 名患者 (8%) 出现 2 级不良事件。所有患者在 8 次给药后均实现了注射病变的局部控制，其中 1 名患者完全消退（平均消退，-25%；范围，-100% 至 4%）。在具有持久局部反应的患者中，肿瘤浸润淋巴细胞可检测到增加。在 1 名患者中（随访 259 天时目标病变 -39%），TCR 测序显示先前存在的克隆型和从头克隆型的扩展，以及编码相同结合序列的大量重排的收敛（表明克隆收敛于抗肿瘤靶标）。单细胞测序在治疗后的外周血中鉴定出这些相同的扩增 TCR 克隆；这些T细胞的Tbet表达显着增强，表明TH1表型。在这项非随机对照试验中，IT GLA-SE与同步放疗的耐受性良好，并且比单独放疗提供了更持久的局部控制。具有持久局部反应的患者表现出 IT T 细胞克隆扩增增强，这些克隆型在循环中的扩增也相应增强。需要进行更多研究来评估 IT GLA-SE 和放疗与全身免疫调节的协同作用。ClinicalTrials.gov 标识符：NCT02180698。

Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts.To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions.This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022.Two doses of IT GLA-SE (5 μg and 10 μg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion.Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes.Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, -25%; range, -100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion -39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype.In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted.ClinicalTrials.gov Identifier: NCT02180698.