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

摘要 前列腺癌，而惰性的性质，有特定的亚型目前与侵略性局部疾病 它们很快就会产生激素抵抗。去势抵抗性疾病（CRPC）患者通常 年轻人和非高加索人，许多人患有局部进展，水肿和疼痛。放射治疗（RT） 提供，但受到程度，以前的暴露和疾病抵抗力的限制。序贯多次化疗 或RT治疗，作为护理标准提供，很难遵守，特别是在低资源人群中。 由于经济和社会原因，这种有症状人群的治疗往往过早终止，或从未开始。 时间限制。需要创新的、更短的、更有效的治疗方法，特别是为了减少 全球癌症护理的合规性和结果。 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）的组合， 称为放射免疫治疗剂量绘制（RAID）技术， 目标中的抗CD 40有效载荷被辐射，并已显示出启动免疫系统， 通过原位疫苗接种可持续地控制肿瘤，即使在不同的治疗方案失败后。此外，委员会认为， 这种联合治疗可以通过短时间的简单干预快速改善生活质量（QoL），副作用较少 抗CD 40的有效载荷远小于静脉内（IV）免疫治疗所需。 该项目的总体目标-由Nanocan Therapeutics Corporation与John 霍普金斯医学，达纳法伯癌症研究所和诺斯韦尔健康-是桥梁临床前工作的第一个 临床试验与创新的RAID技术，并确认其潜力，在原位接种，可以延长 放疗（RT）的使用从姑息性局部治疗到全身疾病控制在一个会话。 iSRB作为种子样基准标记物，通过超声引导直接施用在前列腺肿瘤中。 针. iSRB在CT和KV成像上产生对比度，使RT设置快速; iSRB缓慢释放（20 mcg 每单位15天）的抗CD 40有效载荷直接照射靶，触发原位接种。 该项目的目的是将来自小动物研究的大量安全性和有效性数据转化为单个 部分RT联合缓释肿瘤内抗CD 40递送用于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，以确认已在大量小动物中进行的安全性、免疫原性和药代动力学 工作Mildarin将由Nanocan Therapeutics完成IND填写。FDA批准后， 该项目将包括1期单组开放标签临床试验，寻求确认安全性和数量 CRPR患者所需的iSRB以及RT剂量。该项目可以提供所有需要的数据， II期临床工作旨在为CRPR患者提供一种新的治疗模式。

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.