Phase 1 Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System Tumors

This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7H3-specific chimeric antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into the tumor resection cavity or ventricular system in children and young adults with diffuse intrinsic pontine glioma (DIPG), diffuse midline glioma (DMG), and recurrent or refractory CNS tumors.
A child or young adult meeting all eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meeting none of the exclusion criteria, will have their T cells collected. The T cells will then be bioengineered into a second-generation CAR T cell that targets B7H3-expressing tumor cells. Patients will be assigned to one of 3 treatment arms based on location or type of their tumor. Patients with supratentorial tumors will be assigned to Arm A, and will receive their treatment into the tumor cavity. Patients with either infratentorial or metastatic/leptomeningeal tumors will be assigned to Arm B, and will have their treatment delivered into the ventricular system. The first 3 patients enrolled onto the study must be at least 15 years of age and assigned to Arm A or Arm B. Patients with DIPG will be assigned to Arm C and have their treatment delivered into the ventricular system. The patient's newly engineered T cells will be administered via the indwelling catheter for two courses. In the first course patients in Arms A and B will receive a weekly dose of CAR T cells for three weeks, followed by a week off, an examination period, and then another course of weekly doses for three weeks. Patients in Arm C will receive a dose of CAR T cells every other week for 3 weeks, followed by a week off, an examination period, and then dosing every other week for 3 weeks. Following the two courses, patients in all Arms will undergo a series of studies including MRI to evaluate the effect of the CAR T cells and may have the opportunity to continue receiving additional courses of CAR T cells if the patient has not had adverse effects and if more of their T cells are available.
The hypothesis is that an adequate amount of B7H3-specific CAR T cells can be manufactured to complete two courses of treatment with 3 or 2 doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that B7H3-specific CAR T cells can safely be administered through an indwelling CNS catheter or delivered directly into the brain via indwelling catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study. Secondary aims of the study will include evaluating CAR T cell distribution with the cerebrospinal fluid (CSF), the extent to which CAR T cells egress or traffic into the peripheral circulation or blood stream, and, if tissues samples from multiple timepoints are available, also evaluate disease response to B7-H3 CAR T cell locoregional therapy.

开始日期2019-12-11

申办/合作机构

Seattle Children's Hospital

100 项与 BCB-276 相关的临床结果

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100 项与 BCB-276 相关的转化医学

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100 项与 BCB-276 相关的专利（医药）

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项与 BCB-276 相关的文献（医药）

2025-03-01·NATURE MEDICINE

Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial

Article

作者: Albert, Catherine M ; Kong, Ada ; Hoeppner, Corrine ; Annesley, Colleen ; Foster, Jessica B ; Perez, Francisco A ; Pattabhi, Sowmya ; Seidel, Kristy ; Gust, Juliane ; Gardner, Rebecca A ; Jensen, Michael C ; Wein, Amy ; Lee, Amy ; Huang, Wenjun ; Brown, Christopher ; Ho, On ; Wendler, Jason P ; Park, Julie R ; Leary, Sarah E S ; Beebe, Adam ; Alonso, Marta M ; Lindgren, Catherine ; Ojemann, Jeffrey G ; Orentas, Rimas J ; Thomsen, Alison ; Goldstein, Hannah E ; Dun, Matthew D ; Browd, Samuel R ; Hauptman, Jason S ; Steinmetzer, Leonel ; Holtzclaw, Susan ; Wilson, Ashley L ; Beam, Madison ; Hurst, Diana ; Crotty, Erin E ; Gustafson, Joshua A ; Rawlings-Rhea, Stephanie D ; Vitanza, Nicholas A ; Pinto, Navin ; Ronsley, Rebecca ; Wright, Jason N ; Choe, Michelle

Abstract:

Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG. The primary objectives were to assess feasibility and tolerability, which were both met. Secondary objectives included assessments of CAR T cell distribution and survival. A total of 23 patients with DIPG enrolled, and 21 were treated with repeated doses of ICV B7-H3 CAR T cells using intra-patient dose-escalation regimens without previous lymphodepletion. Concurrent tumor-directed therapy, including re-irradiation, was not allowed while on protocol therapy. We delivered a total of 253 ICV doses and established the highest planned dose regimen, DR4, which escalated up to 10 × 107 cells per dose, as the maximally tolerated dose regimen. Common adverse events included headache, fatigue and fever. There was one dose-limiting toxicity (intratumoral hemorrhage) during DR2. For all treated patients (n = 21), the median survival from their initial CAR T cell infusion was 10.7 months and the median survival from diagnosis was 19.8 months with 3 patients still alive at 44, 45 and 52 months from diagnosis. Ultimately, this completed first-in-human trial shows that repetitive ICV dosing of B7-H3 CAR T cells in pediatric and young adult patients with DIPG is tolerable, including multiyear repeated dosing, and may have clinical efficacy that warrants further investigation on a multisite phase 2 trial. ClinicalTrials.gov registration: NCT04185038.

2023-01-01·Frontiers in oncology

B7-H3-targeted CAR T cell activity is enhanced by radiotherapy in solid cancers.

Article

作者: Wang, Xinhui ; Ferrone, Cristina R ; Arya, Shahrzad ; Jia, Jingyu ; Ferrone, Soldano ; Maggs, Luke ; Ventin, Marco ; Cattaneo, Giulia

Adoptive cell therapy utilizing T cells genetically modified to express a chimeric antigen receptor (CAR) has demonstrated promising clinical results in hematological malignancies. However, solid cancers have not seen a similar success due to multiple obstacles. Investigating these escape mechanisms and designing strategies to counteract such limitations is crucial and timely. Growing evidence in the literature supports the hypothesis that radiotherapy has the potential to enhance the susceptibility of solid tumors to CAR T cell therapy, by overcoming mechanisms of resistance. Radiation treatment can increase the susceptibility of different types of solid cancers (TNBC, HNSCC, PDAC) to B7-H3 CAR T cell-mediated eradication. Multiple mechanisms, including reduced cancer cell proliferation, upregulation of the targeted antigen, modulation of apoptotic molecules may contribute to this signal. The information in the literature and the results we describesupport the ability of radiotherapy to improve the efficacy of CAR T cell therapy in solid tumors.

项与 BCB-276 相关的新闻（医药）

2025-06-10

·今日头条

生存期突破4年创生命奇迹！新型CAR-T疗法为儿童致命脑瘤点亮希望新型CAR-T疗法为儿童致命脑瘤DIPG带来希望，FDA授予其突破性疗法认定。 1. B7-H3 CAR-T细胞疗法 BCB-276通过改造患者T细胞，精准识别并攻击DIPG肿瘤细胞。 2. 显著延长生存期 21名接

生存期突破4年创生命奇迹！新型CAR-T疗法为儿童致命脑瘤点亮希望新型CAR-T疗法为儿童致命脑瘤DIPG带来希望，FDA授予其突破性疗法认定。 1. B7-H3 CAR-T细胞疗法 BCB-276通过改造患者T细胞，精准识别并攻击DIPG肿瘤细胞。 2. 显著延长生存期 21名接受治疗的患者中位生存期达10.7个月，3名患者突破44个月。 3. 高疾病控制率 18名接受评估的患者中，1例部分缓解，15例病情稳定，疾病控制率89%。 4. 国内CAR-T疗法临床实验国内针对多种实体瘤靶点开展CAR-T疗法临床实验。

细胞疗法免疫疗法临床结果突破性疗法ASH会议

2025-06-10

·今日头条

生存期突破4年创生命奇迹！新型CAR-T疗法为儿童致命脑瘤点亮希望

3 名患者在确诊后 44、45 和 52 个月时依然存活，远超 DIPG 患者的传统生存期预期，创下生命奇迹！这意味着，无论患者处于疾病何种阶段，B7-H3 CAR-T 细胞疗法均能显著延长生存期，为儿童致命脑瘤带来新希望！弥漫性内在性脑桥胶质瘤（DIPG），这个令医学界谈之色变的 “儿童癌症杀手”，是一种侵袭性极强的中枢神经系统肿瘤，生存率极低，即使在美国，它的 5年存活率依然<1% 。主要因为这类肿瘤无法手术，也无法大剂量放疗。虽然我们有越来越多的治疗手段，但对多数脑瘤来说，高质量手术和放疗依然是取得良好治疗效果的前提。遗憾的是，脑干区域控制着人体的核心功能，包括呼吸，心跳，消化等。因此，想要完全消灭肿瘤细胞，而不破坏任何关键神经，是不可能完成的任务。幸运的是，无论这条路有多艰辛，总有人为了想办法把这些孩子们从死亡线上拉回来这个特殊使命前仆后继不断尝试，坚持到底。值得振奋的是，美国西雅图儿童医院的新型CAR-T疗法取得重大突破：近日，美国食品药品监督管理局（FDA）授予自体 B7-H3 靶向 CAR-T 细胞疗法 BCB-276 突破性疗法认定，用于治疗弥漫性内生性脑桥胶质瘤（DIPG）的儿童患者。这一决定不仅为绝望中的患儿家庭点亮了希望之光，更标志着人类在攻克这一 “儿童癌症杀手” 的道路上迈出了关键一步。生存期突破52个月，创生命奇迹！新型CAR-T疗法为儿童致命脑瘤带来新希望 BCB-276 是一款全新的靶向 B7-H3 的 CAR-T 细胞疗法，其作用机制堪称 “精准制导”。B7-H3 蛋白在 DIPG 肿瘤细胞表面高度表达，而 BCB-276 通过对患者自身 T 细胞进行改造，使其能够精准识别并结合 B7-H3，激活免疫系统对肿瘤细胞发起攻击。这种高度特异性的靶向治疗方式，既能有效杀伤癌细胞，又能最大程度减少对正常组织的损伤，为攻克 DIPG 提供了全新的思路和策略。此次FDA授予突破性治疗制定是基于在美国知名的西雅图儿童医院开展的1 期代号为BrainChild-03 试验 (NCT04185038) 的卓越数据支持。这项研究也发表在了国际顶级期刊《自然医学》上，引起巨大轰动！这项研究共入组了 23 名符合条件的DIPG 患者，其中 21 名患者接受了重复剂量的 ICV B7-H3 CAR-T 细胞治疗。值得一提的是，和传统的CAR-T疗法给药方式不同， BCB-276率先通过植入式分流器对中枢神经系统脑室细胞进行重复给药。这可以增强肿瘤的可及性，并实现治疗细胞的分区，从而提高安全性和疗效，无需进行全身淋巴细胞清除化疗。通过采用递归、分次剂量的细胞来增强和维持效力，确保肿瘤床在可控的数量和持续时间内持续充满具有生物活性的抗肿瘤效应细胞。临床试验结果令人振奋！所有接受治疗的 21 名患者，自初次 CAR-T 细胞输注后的中位生存期达到 10.7 个月，从确诊到死亡（或幸存者最后一次联系）的中位时间更是长达 19.8 个月。其中，3 名幸运的患者在确诊后 44.6、45.6 和 52.5 个月时依然存活，远超 DIPG 患者的传统生存期预期。进一步分析发现，在疾病进展前接受治疗的 9 名患者，首次 CAR-T 细胞输注后的中位生存期为 13.6 个月；而进展后才开始治疗的 12 名患者，中位生存期也达到 9.4 个月。这表明，无论患者处于疾病何种阶段，B7-H3 CAR-T 细胞疗法均能显著延长生存期。共有18名患者接受了足够的CAR T细胞输注，可以进行神经影像评估。结果显示：1例部分缓解（PR，6%），15例病情稳定（SD，83%），疾病控制率高达89% ！特别值得分享的是，两名幸存患者仍在接受方案治疗：S021（2 岁时诊断出患有 H3F3A K27M 突变的脑桥 DMG）已在 37.5 个月内接受了 81 剂（共 3 × 10 9个 CAR-T 细胞），S027（5 岁时进行非诊断性活检）在31.5个月内已接受了 39 剂（共 9.5 × 108 CAR T 细胞) . 安全性上，B7-H3 CAR-T 细胞疗法同样表现优异。常见不良事件主要为头痛、疲劳和发烧，且多为 1 级或 2 级轻微症状。仅在 DR2 阶段出现 1 例剂量限制性毒性（肿瘤内出血），未对整体安全性构成重大威胁。这意味着患儿在接受治疗时，无需承受难以忍受的副作用，为长期治疗提供了坚实保障。西雅图儿童医院首席执行官 Jeff Sperring 博士表示：“这一认定是我们在儿童脑癌研究领域的重要里程碑，我们将与 BrainChild Bio 紧密合作，加速 CAR-T 细胞疗法的研发，用科学的力量为患儿带来治愈的希望。喜讯！国内多家癌症中心启动CAR-T细胞疗法临床实验上述研究中的CAR-T疗法虽然处于实体瘤临床实验阶段，但实际上随着CAR-T代数的更迭，CAR-T在增殖、细胞因子释放等方面有了明显改进，众多临床试验已将CAR-T用于实体瘤的治疗，并有幸运的患者得到完全缓解，晚期实体肿瘤患者迎来暖春！这些研究希望能给病友们带来新的希望。好消息是，这些国际前沿的T疗法正在进行临床实验招募各类实体肿瘤患者，想寻求 CAR-T、TCR-T、TIL 等细胞疗法及其他国内外治疗新技术帮助，且经济条件允许的情况下可提交病历至全球肿瘤医生网申请。此外，目前针对以下实体瘤靶点，国内的多项CAR-T疗法正在进行临床实验： Claudin18.2：用于胃癌，胰腺癌等；间皮素（mesothelin）：用于治疗间皮瘤、胰腺癌、卵巢癌、肺癌； CEA：用于治疗肺癌、结肠癌、胃癌、乳腺癌和胰腺癌； MUC-1：用于治疗肝癌、肺癌、胰腺癌、结肠癌、胃癌 ; GPC3：用于治疗肝癌 ; GUCY2C：用于结直肠癌； EGFＲvII：用于治疗神经胶质瘤、头颈部肿瘤； B7-H3：用于治疗尤文肉瘤、横纹肌肉瘤、肾母细胞瘤、神经母细胞瘤和髓母细胞瘤以及特别难以治疗的脑干肿瘤（DIPG）； PSMA：用于前列腺癌等。在细胞疗法出现之前,包括晚期胃腺癌、胰腺癌在内的实体瘤通常是采用手术、放化疗进行治疗,其中胃腺癌的发生率占胃恶性肿瘤的95%,胰腺癌更是常见肿瘤中恶性程度最高的肿瘤,中位生存期和5年生存率都远远低于其他肿瘤,号称“癌中之王”。但是大部分患者术后会出现局部复发或转移,另外,这类恶性肿瘤对放化疗的敏感性也不高。所以基于目前的标准疗法,治疗效果并不理想,而且预后极差。免疫疗法的出现，将给更多的晚期患者带来长期生存的希望和奇迹。我们坚信，在完善的细胞免疫监管制度出台后，国家将放开细胞免疫治疗的大门造福更多的癌症患者，我们国家的细胞免疫疗法也会大步登上国际舞台！

细胞疗法免疫疗法临床1期突破性疗法ASH会议

2025-05-28

·同写意

里程碑突破！全球首个实体瘤CAR-T有望到来

ASCO会议优先审批细胞疗法孤儿药免疫疗法

100 项与 BCB-276 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
儿童中枢神经系统肿瘤	临床1期	美国	Seattle Children's Hospital	2019-12-11
脉络丛癌	临床1期	美国	Seattle Children's Hospital	2019-12-11
弥漫内生性脑桥神经胶质瘤	临床1期	美国	Seattle Children's Hospital	2019-12-11
弥漫性中线胶质瘤	临床1期	美国	Seattle Children's Hospital	2019-12-11
室管膜瘤	临床1期	美国	Seattle Children's Hospital	2019-12-11
髓母细胞瘤	临床1期	美国	Seattle Children's Hospital	2019-12-11
松果体母细胞瘤	临床1期	美国	Seattle Children's Hospital	2019-12-11
中枢神经系统横纹肌瘤	临床1期	美国	Seattle Children's Hospital	2019-12-11

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04185038 (BrainChild-03, Nat Med) 人工标引	临床1期	弥漫内生性脑桥神经胶质瘤	21	B7-H3 CAR T cells	齋鑰廠衊網構糧製遞齋(艱糧窪糧齋窪遞築鏇選) = The primary objectives were to assess feasibility and tolerability, which were both met. 蓋顧顧顧積淵蓋構築繭 (齋壓膚鬱觸衊鹹餘築襯 ) 达到更多	积极	2025-01-07
NCT04185038 (BrainChild-03, AACR2023) 人工标引	临床1期	弥漫性中线胶质瘤 \| 中枢神经系统肿瘤	22	B7-H3 CAR T cell	鬱鹹窪獵鑰淵鹽衊醖壓(顧鬱觸廠獵餘獵醖壓築) = 齋蓋憲鏇構淵餘範窪範範衊鹽淵獵簾鏇選膚膚 (膚膚蓋鹹膚積壓顧範窪 ) 更多	积极	2023-04-14