Leveraging doxorubicin immune-modulation, blood-brain barrier opening, and personalized medicine for effective immunotherapy in glioblastoma. A mechanistic approach and pharmacokinetic trial.

利用阿霉素免疫调节、血脑屏障开放和个性化医疗对胶质母细胞瘤进行有效的免疫治疗。

• 批准号: 10305132
• 负责人: Adam M Sonabend
• 金额: $ 25.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10305132
• 关键词: Address; Adjuvant; Antibodies; Antigen Presentation; Antitumor Response; Attenuated; Autologous; Biological; Biological Markers; Biopsy; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Breast Cancer Patient; Bypass; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Characteristics; Clinical; Clinical Trials; Cohort Studies; Combined Modality Therapy; Contralateral; Devices; Dose; Doxorubicin; Drug Kinetics; Drug or chemical Tissue Distribution; Excision; Exhibits; Exposure to; Failure; Glioblastoma; Glioma; Goals; Heterogeneity; Human; Immune response; Immunohistochemistry; Immunologic Surveillance; Immunotherapy; Impairment; Implant; Infiltration; Interferons; Intravenous; Lead; Long-Term Survivors; MAP Kinase Gene; Maintenance; Measures; Microbubbles; Molecular; Mus; Myeloid Cells; Neoadjuvant Therapy; Operative Surgical Procedures; Outcome; Patient Recruitments; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Property; Prospective cohort; Recurrence; Regimen; Reporting; Research; Role; Safety; Signal Transduction; Site; Sonication; Specimen; Stains; Survival Analysis; System; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Time; Tissues; Tumor Antigens; Tumor Immunity; Tumor Tissue; Ultrasonography; Work; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; anti-tumor immune response; base; blood-brain barrier disruption; brain tissue; cohort; cranium; cytotoxic; density; drug distribution; genetic signature; immune checkpoint blockade; immunogenic; immunogenicity; immunoregulation; implantable device; improved; improved outcome; in vivo evaluation; innovation; neoplastic cell; novel; objective response rate; patient subsets; personalized medicine; pre-clinical; predicting response; primary endpoint; response; secondary endpoint; standard of care; survival prediction; trial comparing; tumor; tumor growth; tumor-immune system interactions

ABSTRACT Despite preclinical promise and occasional long(er) term tumor growth control in subsets of patients, anti-PD1 checkpoint blockade (aPD1) has failed to improve outcome in glioblastoma (GBM). The failure to demonstrate a benefit to an anti-PD1 antibody (aPD1) may be due to 1) an immunosuppressive microenvironment with few immunogenic tumor cells; 2) insufficient aPD1 penetration across the blood-brain barrier (BBB), which fail to reach the infiltrating tumor cells in the peritumoral brain; and 3) molecular heterogeneity of GBM. Here we systematically address each of these challenges. We aim to elicit robust anti-tumoral response to Balstilimab (Agenus Bio), a novel aPD1 antibody by modulating the immune response by low doses of doxorubicin as has been shown previously. To allow for adequate drug tissue penetration, we will transiently disrupt the blood-brain barrier by a skull implantable ultrasound device (SonoCloud-9) in association with intravenous microbubbles (US/MB). In our ongoing research and clinical trials we have shown the feasibility of this approach including targeted biopsies of enhancing and non-enhancing tissue and measure drug tissue distribution. Lastly, we aim at identifying molecular characteristics that will allow to predict a benefit from aPD1 immunotherapy based on our prior work where we have identified MAPK activation (pERK staining) as a putative biomarker. We will firstly refine the sequence of DOX & aPD1 administration in preclinical models. Second, for verification and optimization we will treat a few pilot patients in the lead-in phase of our trial. Third, the optimized regimen will be tested in a multi-cohort study in patients with recurrent GBM who will be treated by DOX and the aPD1 Balstilimab (DOX+aPD1). Primary endpoints are tumor immune response in the resection specimen and/or peripheral immune response, drug concentrations in enhancing and non-enhancing brain tissue (targeted biopsies at the time of resection) and safety. Clinical outcome and biomarkers are secondary endpoints. Four cohorts of patient will be examined where DOX/aPD1 treatment starts at different time points: Induction (neoadjuvant, prior to resection); or intraoperatively upon resection, each with and without US/MB. A non-interventional standard of care cohort will serve as control. Our proposal has 3 specific aims: SA1: Characterize & optimize the effect of DOX + aPD1 on anti-tumoral immunity in GBM. SA2: Determine the effect of US/MB on the concentration of DOX + aPD1 in the human brain and anti-tumoral immune response in GBM. SA3: Investigate whether tumor pERK/MAPK activation predicts GBM response to DOX + aPD1. Successful completion will determine the i) value of immune modulation by DOX and aPD1; ii) the value of induction (pre-resection) treatment and in vivo evaluation of anti-tumor immune response; iii) the value (or absence thereof) of BBB-opening for aPD1 efficacy; and iv) whether pERK predicts response and identifies patients that will benefit from treatment.

抽象的 尽管临床前的承诺和患者子集的偶尔长（ER）期限肿瘤的生长控制，抗PD1 检查点封锁（APD1）未能改善胶质母细胞瘤（GBM）的结果。未能证明 抗PD1抗体（APD1）的好处可能是由于1）较少的免疫抑制微环境 免疫原性肿瘤细胞； 2）APD1在血脑屏障（BBB）中的渗透不足，但无法 到达周围脑中浸润的肿瘤细胞； 3）GBM的分子异质性。我们在这里 系统地解决这些挑战中的每一个。我们的目的是引起对巴尔斯蒂单抗的强大抗肿瘤反应 （Agenus bio），一种新型的APD1抗体，通过通过低剂量的阿霉素调节免疫反应 以前已显示。为了允许足够的药物组织穿透，我们将瞬时破坏血脑 与静脉微泡有关的颅骨植入超声设备（Sonocloud-9）的屏障 （美国/MB）。在我们正在进行的研究和临床试验中，我们显示了这种方法的可行性 有针对性的活检增强和非增强组织并测量药物组织分布。最后，我们的目标 在识别分子特征方面，该特征将允许基于APD1免疫疗法的益处 我们先前已经将MAPK激活（PERK染色）确定为推定生物标志物的工作。我们首先 完善临床前模型中DOX和APD1给药的序列。第二，用于验证和 优化我们将在试验阶段对待一些试验患者。第三，优化的方案将是 在一项多功能研究中对复发性GBM患者进行了测试，这些患者将由DOX和APD1 Balstilimab治疗 （DOX+APD1）。主要终点是切除试样中的肿瘤免疫反应和/或外围 免疫反应，增强和非增强脑组织的药物浓度（针对性的活检 切除时间）和安全性。临床结果和生物标志物是次要终点。四个患者 将检查DOX/APD1治疗从不同时间点开始的地方：诱导（NeoAdjuvant，在 切除）;或术中切除术，每种都有和没有我们/MB。非惯用标准 护理队列将作为控制。我们的建议具有3个具体目标：SA1：表征并优化 DOX + APD1在GBM中的抗肿瘤免疫力上。 SA2：确定US/MB对浓度的影响 人脑中的DOX + APD1和GBM中的抗肿瘤免疫反应。 SA3：调查肿瘤是否 PERK/MAPK激活预测GBM对DOX + APD1的响应。成功完成将决定I） DOX和APD1的免疫调节值； ii）诱导的价值（切除前）治疗和体内 评估抗肿瘤免疫反应； iii）BBB开放式APD1功效的价值（或其不存在）； iv）PERK是否可以预测反应并确定将从治疗中受益的患者。