Treatment of Glioblastoma: the combination of fluorescence guided surgery and photodynamic therapy

胶质母细胞瘤的治疗：荧光引导手术与光动力疗法的结合

• 批准号: 10079083
• 负责人: WILLIAM R POTTER
• 金额: $ 40万
• 依托单位: PHOTOLITEC, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079083
• 关键词: Administrative Personnel; Area; Biodistribution; Biological; Blood - brain barrier anatomy; Brain; Brain region; C14 isotope; Canis familiaris; Cell Culture System; Cells; Cerebrum; Chemistry; Chemotherapy and/or radiation; Clinic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Custom; Data; Devices; Dimerization; Disease; Distant; Dose; Drug Formulations; Drug Kinetics; Drug Stability; Effectiveness; Excision; Exhibits; Fluorescence; Funding; Glioblastoma; Glioma; Goals; Growth; Guidelines; Head Cancer; Histopathology; Human; Image; Image-Guided Surgery; Implant; In Vitro; Incidence; Institutional Review Boards; Lasers; Left; Letters; Light; Methods; Modeling; Modernization; Mus; Nature; Neck Cancer; Neurosurgeon; Operative Surgical Procedures; Organ; Orphan Drugs; PUVA Photochemotherapy; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Photosensitization; Photosensitizing Agents; Phototoxicity; Property; Published Comment; Radiation; Rattus; Recurrence; Recurrent tumor; Research Personnel; Residual Tumors; Residual state; Review Committee; Roswell Park Cancer Institute; STAT3 gene; Scientist; Skin; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Specificity; Supervision; Technology; Therapeutic; Time; Tissue Sample; Toxic effect; Translating; Treatment Efficacy; absorption; cancer imaging; cancer therapy; chemotherapy; cost; crosslink; experience; experimental study; fluorescence imaging; fluorescence-guided surgery; iatrogenic injury; improved outcome; in vivo; innovation; instrument; interest; meetings; migration; optimal treatments; patient population; pharmacokinetics and pharmacodynamics; phase I trial; pre-clinical; preclinical study; response; stem; three dimensional cell culture; tumor; tumor growth; uptake

ABSTRACT: The previously funded STTR (Fast Track Phase I/II, preclinical studies) project (R41/R42 CA173980-01A) helped us in developing desired NIR PS (Photobac) with a great potential for both cancer imaging and therapy. An efficient method for the synthesis of Photobac was also established in a GMP facility. Following the US FDA guidelines, the pharmacokinetic (PK), pharmacodynamic (PD) and toxicity of Photobac in various doses were also investigated in mice, rats and dogs. Histopathology results did not show any organ toxicity. Photobac even at a 20-fold higher than the therapeutic dose (single dose needed for the treatment) was not lethal. No metabolite formation and organ toxicity even at higher than the desired therapeutic dose was observed. The biodistribution of C-14 Photobac at variable time points was also determined in mice and rats [7, 8]. Results with C-14 Photobac in rats and fluorescence results in mice suggest that Photobac crosses the blood brain barrier (BBB). A positive pre-IND response from the US FDA on our request for the use of Photobac to treat Gliomas was pleasing & exciting (Application # PIND 136905). As suggested by the FDA review committee, the revision of human patient Phase I protocol has been accomplished. NIR PS Photobac has also received an “Orphan Drug” status from the US FDA for imaging and therapy of Glioblastoma (fluorescence-guided surgery + PDTof recurrence tumors) (# DRU-2017-6153), which further encouraged us to move this technology to Phase I human clinical trials. To achieve our goal, the proposed study (SBIR: Preclinical and Clinical)) has been divided into following aims: Aim 1 (a): To investigate the PDT efficacy of Photobac in rat glioma model and using Simphotek’s proprietary computational device FPDosi™ (Beeson et al. J. Biomed. Opt. 24(3), 035006, 2019) compare light dose to experiments. Details are presented in the letter of support from Simphotek. Aim 1 (b): To compile the Photobac CMC (chemistry, manufacturing and control), drug-formulation, stability of drug substance and drug product, analytical details, PK/PD, toxicity, in vitro & in vivo data and Phase I clinical protocol for an IND submission to the US FDA for fluorescence image guided surgery + PDT of glioblastoma. The cost of the IND submission will be paid by Photolitec, LLC. Aim 2: To compile the details of PS (Photobac)-customized NIR laser instrument (787 nm, developed with the help of Biolitec) following the US FDA guidelines, and submit it for approval (combined IND-Aim 1]. Aim 3: To perform Phase I trial with Photobac-PDT, fluorescence-guided treatment (surgery + PDT) of glioblastoma at a single light dose and variable drug doses for selecting the best treatment parameters. Aim 4: To provide tissue samples from glioblastoma, corresponding non-tumor tissue, untreated tumors, Photobac-PDT treated tumors and recurrent tumors after previous surgery, chemotherapy, radiation and chemotherapy treatment, for Photobac specificity using 3D cell-culture system, and STAT3 crosslinks analysis. Aim 5: Establish a correlation between the cell-uptake on patients’ tumors (at various stages) implanted in mice, photo-induced STAT3 dimerization and a long-term PDT response [7]. Translate these findings to enhance the optimal treatment parameter(s) of glioblastoma patients.

抽象的： 此前资助的STTR（Fast Track Phase I/II，临床前研究）项目（R41/R42 CA173980-01A） 帮助我们开发了所需的 NIR PS (Photobac)，在癌症成像和治疗方面具有巨大潜力。 GMP 设施中还建立了一种有效合成 Photobac 的方法。追随美国 FDA指南，不同剂量的Photobac的药代动力学（PK）、药效学（PD）和毒性 还在小鼠、大鼠和狗身上进行了研究。组织病理学结果未显示任何器官毒性。光巴克 即使比治疗剂量（治疗所需的单剂量）高 20 倍也不会致命。不 即使在高于所需治疗剂量的情况下，也观察到代谢物形成和器官毒性。这 还在小鼠和大鼠中测定了 C-14 Photobac 在不同时间点的生物分布 [7, 8]。结果 大鼠体内的 C-14 Photobac 和小鼠的荧光结果表明 Photobac 穿过血脑 屏障（BBB）。 美国 FDA 对我们使用 Photobac 治疗神经胶质瘤的请求做出了积极的预 IND 回应 令人愉悦且令人兴奋（申请号 PIND 136905）。根据 FDA 审查委员会的建议，修订 人类患者 I 期方案已经完成。 NIR PS Photobac 还获得了“孤儿奖” 美国 FDA 授予的用于胶质母细胞瘤成像和治疗的“药物”状态（荧光引导手术 + 复发肿瘤的 PDT）（# DRU-2017-6153），这进一步鼓励我们将这项技术转移到 I 期人体临床试验。为了实现我们的目标，拟议的研究（SBIR：临床前和临床）） 分为以下目标： 目标 1 (a)：研究 Photobac 在大鼠神经胶质瘤模型中的 PDT 功效，并使用 Simphotek 的专有技术 计算设备 FPDosi™（Beeson 等人 J. Biomed. Opt. 24(3), 035006, 2019）将光剂量与 实验。 Simpotek 的支持信中提供了详细信息。目标 1 (b)：编制 Photobac CMC（化学、制造和控制）、药物制剂、原料药和药物的稳定性 产品、分析细节、PK/PD、毒性、体外和体内数据以及 IND 的 I 期临床方案 向美国FDA提交胶质母细胞瘤荧光图像引导手术+PDT的申请。 IND 的费用 提交费用将由 Photolitec, LLC 支付。 目标 2：编制 PS (Photobac) 定制近红外激光仪器（787 nm，与 Biolitec 的帮助）遵循美国 FDA 指南，并提交审批（合并 IND-Aim 1]。 目标 3：利用 Photobac-PDT 进行 I 期试验，荧光引导治疗（手术 + PDT） 胶质母细胞瘤在单一光剂量和可变药物剂量下选择最佳治疗参数。 目标 4：提供来自胶质母细胞瘤、相应非肿瘤组织、未经治疗的肿瘤、 Photobac-PDT 治疗的肿瘤以及先前手术、化疗、放疗后复发的肿瘤 化疗治疗，使用 3D 细胞培养系统进行 Photobac 特异性，以及 STAT3 交联分析。 目标 5：建立植入患者肿瘤（不同阶段）的细胞摄取之间的相关性 小鼠，光诱导 STAT3 二聚化和长期 PDT 反应 [7]。将这些发现转化为 增强胶质母细胞瘤患者的最佳治疗参数。