Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin’s antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin’s immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes. This study was registered with ClinicalTrial.gov, number NCT02406781.

中文翻译：

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节拍曲贝替定联合低剂量环磷酰胺对肉瘤微环境的影响及其与临床结果的相关性：TARMIC 研究结果

软组织肉瘤（STS）是一种多样化的间叶性肿瘤，在晚期阶段几乎没有治疗选择。曲贝替定已获得全球批准用于治疗对蒽环类药物治疗耐药的 STS 患者。最近的临床前数据表明，曲贝替定的抗肿瘤活性不仅限于肿瘤细胞，还影响肿瘤微环境（TME），特别是影响肿瘤相关巨噬细胞及其促肿瘤功能。我们提出了 I/II 期结果，评估节拍曲贝替定和低剂量环磷酰胺联合用药对晚期肉瘤患者 TME 的影响。50 名患者参与：20 名患者参加 I 期，30 名患者参加 II 期。使用基线和周期第二天的连续肿瘤样本评估了 28 名患者的 TME 变化。与治疗前相比，治疗 4 周后，28 名患者中有 9 名患者的肿瘤病变活检样本中的 CD68 + CD163 + 巨噬细胞显着减少。其中 11 名患者的基线 CD8 + T 细胞存在增加。总之，高达 57% 的患者表现出阳性免疫反应，其特征是治疗后 M2 巨噬细胞减少或 CD8 + T 细胞增加。TME 的这种积极转变与临床获益和无进展生存期的改善相关。这项研究首次提供了曲贝替定对晚期 STS 患者免疫学作用的前瞻性证据，强调了 TME 调节与患者预后之间的关系。本研究已在 ClinicalTrial.gov 注册，编号为 NCT02406781。