Radio-immunotherapy dose-painting (RAID) treatment for hormonal resistant prostate cancer

摘要 前列腺癌本质上相当迟缓，具有侵袭性局部疾病的特殊亚型。 很快就会对荷尔蒙产生抵抗力。抗去势疾病(CRPC)患者通常 年轻人和非高加索人，许多人患有局部进展、浮肿和疼痛。放射治疗(RT) 提供的，但受限于疾病的程度、以前的暴露和抵抗力。序贯多次化疗 或者，作为标准护理提供的RT治疗很难遵守，特别是在资源匮乏的人群中。 对这些有症状的人群的治疗往往过早终止，或者从未开始，原因是经济和 时间限制。需要创新、更短、更有效的治疗方法，特别是为了减少 全球癌症护理的遵从性和结果。 在广泛的临床前工作中，RT与免疫原性智能放射治疗材料(ISRB)的结合， 被称为放射免疫治疗剂量涂抹(RAID)技术，带来肿瘤内的缓释 靶体内的抗CD40有效载荷，受到辐射并已显示出启动免疫系统并创建 即使在不同的治疗方案失败后，也可以通过原位疫苗进行可持续的肿瘤控制。此外， 这种联合治疗可以以较少的副作用，通过短暂的简单干预，快速提高生活质量(QOL) 抗CD40有效载荷远小于静脉(IV)免疫治疗所需。 该项目的总体目标--由Nanocan治疗公司与John合作提出 霍普金斯医学、Dana-Farber癌症研究所和Northwell Health-将把临床前工作与第一 使用创新的RAID技术进行临床试验，并确认其可扩展的原位疫苗接种的潜力 放射治疗(RT)的使用，从姑息性局部治疗到全身性疾病控制在一次会议上。 在超声引导下，iSRB作为种子样的基准标记物直接用于前列腺癌。 针头。ISRB在CT和KV成像上产生对比度，使RT设置快速；iSRB缓慢释放(20mcg 每单位超过15天)抗CD40有效载荷直接照射到被照射的目标，触发原位接种。 这个项目的目的是从小动物研究中翻译出广泛的安全性和有效性数据。 部分RT联合肿瘤内缓释抗CD40给药用于CRPC患者的首次人体试验。 第一部分将用于将iSRB优化为cGMP产品，并确认在 猴子确认安全性、免疫原性和药代动力学已在广泛的小动物中进行 工作。里程碑将由Nanocan治疗公司完成IND填充。在FDA批准后，第二部分 该项目将包括第一阶段单臂开放标签临床试验，寻求安全性和数量的确认 以及CRPR患者所需的RT剂量。该项目可以为计划提供所需的所有数据 AIMS的第二阶段临床工作为CRPR患者提供了一种新的治疗范式。

ABSTRACT Prostate cancer, rather indolent by nature, has specific subtypes present with aggressive locoregional disease that are quickly becoming hormonal resistant. Patients with castrate-resistant disease (CRPC) are generally younger and non-Caucasian, and many suffer from local progression, edema, and pain. Radiotherapy (RT) is offered but limited by the extent, former exposure, and resistance of disease. Sequential multiple chemotherapy or RT treatments, offered as standard of care, are hard to comply to, especially in low-resource populations. Treatment of this symptomatic population is often terminated prematurely, or never started, due to financial and time restrictions. Innovative, shorter more efficient treatments are needed, especially to reduce disparities in compliance and outcomes of global cancer care. In extensive preclinical work, the combination of RT with immunogenic smart radiotherapy materials (iSRBs), addressed as radio-immunotherapy dose-painting (RAID) technology, brings intra-tumoral slow-release antiCD40 payload in the target that gets irradiated and has shown to prime the immune system and create sustainable tumor control by in situ-vaccination, even after different therapeutic options have failed. Moreover, this combination treatment can improve quality of life (QoL) fast by a short simple intervention with fewer side effects, having an antiCD40 payload far smaller than needed in intravenous (IV) immunotherapy. The overall goal of this project - proposed by Nanocan Therapeutics Corporation in collaboration with John Hopkins Medicine, Dana-Farber Cancer Institute and Northwell Health - is to bridge preclinical work to the first clinical trial with the innovative RAID technology and confirm its potential for in situ-vaccination that can extend the use of radiotherapy (RT) from palliative local treatment to systemic disease control in one session. The iSRBs are as seed-like fiducial markers administered directly in the prostate tumor by ultrasound guided needles. The iSRBs create contrast on CT and KV imaging making RT set-up fast; iSRBs slowly release (20mcg per unit over 15 days) anti-CD40 payload directly the target which gets irradiated, triggering in situ-vaccination. The purpose of this project is to translate extensive safety and efficacy data from small animal studies of single fraction RT combined with slow released intra-tumoral antiCD40 delivery to a first human trial for CRPC patients. The first part will be used to optimize iSRBs into a cGMP product, and confirmation of larger volume testing in monkeys to confirm safety, immunogenicity, and pharmacokinetics already performed in extensive small animal work. Milestones will complete IND filling by Nanocan Therapeutics. After FDA approval, second part of the project will encompass the Phase 1 single arm open label clinical trial seeking confirmation of safety and number of iSRBs as well as RT dose needed in CRPR patients. This project can provide all needed data for planned Phase II clinical work in aims offering a novel treatment paradigm for CRPR patients.