复发性脑肿瘤是儿童癌症死亡的主要原因。色氨酸2,3-双加氧酶（IDO）是一种可靶向调控的新陈代谢检查点，据临床前模型显示，该检查点可以通过化疗抑制抗肿瘤免疫反应。我们进行了一项1期临床试验（NCT02502708），评估了口服IDO通路抑制剂indoximod对复发性脑肿瘤或新诊断的弥漫性髓母质胶质瘤（DIPG）患儿的疗效。我们分别为indoximod与口服依托莫唑胺（200 mg/m2/日x5天，28天为一个周期）和姑息性立体定向放疗进行了剂量寻找试验。我们在基线和每月采集血样进行单细胞RNA测序，同时进行单细胞T细胞受体测序。共有81位患者接受了以indoximod为基础的联合疗法。中位随访时间为52个月（范围39-77个月）。我们尚未达到可耐受的最大剂量，药物剂量确定为儿童19.2 mg/kg/次，每日两次。所有复发患者的中位总生存期为13.3个月（n=68，范围0.2-62.7），DIPG患者的中位总生存期为14.4个月（n=13，范围4.7-29.7）。在n=26个显示出客观反应证据（部分或混合反应）的患者中，中位总生存期超过非反应患者的3倍（25.2个月，范围5.4-61.9，p=0.006）（n=37，中位总生存期为7.3个月，范围0.2-62.7）。有4位患者的无活动性疾病持续超过36个月。单细胞测序证实了新近出现的循环CD8 T细胞克隆型，表现出较晚期效应表型。indoximod耐受性良好，可与化疗和放疗安全联合使用。初步的有效性证据为儿童脑肿瘤的2/3期试验提供了支持。© 2023作者。奥克斯福大学出版社代表神经肿瘤学会发表。

Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy.We conducted a Phase 1 trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing.Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n=68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n=13, range 4.7-29.7) for DIPG. The subset of n=26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p=0.006) compared to n=37 non-responders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype.Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase 2/3 trials for pediatric brain tumors.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.