Transformative personalized vascular disrupting cancer immunotherapy

描述（由申请人提供）：虽然大多数抗癌治疗都是直接针对肿瘤细胞设计的，但有很强的理由将肿瘤血管（TV）作为目标。血管特异性治疗工具的发展受到以下因素的阻碍：(a)缺乏靶点，(b)缺乏具有最佳亲和力和特异性的试剂，以及(c)由于快速清除和/或中和抗体的发展，它们的作用时间较短。本提案旨在解决目前肿瘤血管治疗领域的局限性，并产生一种适用于大多数肿瘤类型的自体过继血管破坏淋巴细胞免疫治疗的强大而个性化的新方法。T细胞将用慢病毒载体进行工程改造，以表达嵌合免疫受体（CIRs），融合分子包括细胞外单链可变片段（scFv）抗体结构域和胞质内CD3， CD28和4-1BB信号域，以实现稳健的T细胞激活。来自患者的淋巴细胞将被基因重新编程，以识别、激活和破坏肿瘤血管系统。这种方法结合了细胞毒性T细胞的敏感性和力量与scFv的特异性，并将释放肿瘤血管的急性移植排斥反应的力量。除了特异性和安全性外，这种方法还具有耐久性和长期记忆。已经开发的针对肿瘤血管表面蛋白TEM1、TEM7R和PSMA的CIRs将用于验证该方法，而针对PI实验室确定的其他肿瘤血管靶点的scFv将被开发。该项目的成功完成将为临床带来模块化CIRs组合，用于最常见和最难治性肿瘤的个性化血管免疫治疗。通过在两个不同的CIRs中物理分离CD3和CD28/4-1BB结构域，每个CIRs识别不同的肿瘤血管靶标，需要同时识别两种不同的肿瘤血管抗原来激活T细胞，从而最大限度地提高安全性。这两个靶点在正常组织中共表达的可能性可以忽略不计，从而使治疗窗口最大化。在工程T细胞中整合自杀基因将提供额外的安全性，这也将允许开发PET成像来实时跟踪体内T细胞的运输。PET成像的平行发展，能够用与CIR相同的scFv显示肿瘤血管目标，这将使我们能够选择适当的CIRs组合进行个性化治疗和监测治疗。鉴于肿瘤血管破坏的力量及其在大多数常见癌症类型共有的广泛靶点上的适用性，这种方法的影响可能正在发生变化。所提出的方法可以切实可行地进入临床，提供高度个性化的癌症治疗无与伦比的力量。

DESCRIPTION (provided by applicant): While the majority of anticancer therapeutic efforts are designed to directly target tumor cells, there is a strong rationale for targeting the tumor vasculature (TV) instead. The development of vascular-specific tools for therapy has been hindered by (a) the paucity of targets, (b) lack of reagents with optimal affinity and specificity, and (c) their short-lived action due to rapid clearance and/or development of neutralizing antibodies. This proposal aims to solve current limitations in the field of cancer vascular therapy and generate a novel powerful and personalized approach of autologous adoptive vascular disrupting lymphocyte immunotherapy applicable to most tumor types. T cells will be engineered with lentiviral vectors to express chimeric immunoreceptors (CIRs), fusion molecules comprising an extracellular single chain variable fragment (scFv) antibody domain and intracytoplasmic CD3, CD28 and 4-1BB signaling domains for robust T-cell activation. Patient-derived lymphocytes will be genetically reprogrammed to recognize, get activated by and destroy specifically the tumor vasculature. This approach combines the sensitivity and power of cytotoxic T cells with the specificity of scFv, and will unleash on the tumor vasculature the power of acute transplant rejection. Besides specificity and safety, this approach offers durability and long-term memory. CIRs already developed against the tumor vascular surface proteins TEM1, TEM7R and PSMA will be used to validate the approach, while scFv against additional tumor vascular targets identified by the PI's lab and others will be developed. The successful completion of the project will bring to the clinic combinations of modular CIRs for personalized vascular immunotherapy for most common and most recalcitrant tumors. Safety will be maximized by requiring simultaneous recognition of two distinct tumor vascular antigens for T cell activation, by physically separating CD3 from CD28/4-1BB domains in two distinct CIRs, each recognizing a different tumor vascular target. The likelihood of both targets to be co-expressed in normal tissues is negligible, thereby maximizing the therapeutic window. Additional safety will be provided by the integration of a suicide gene in engineered T cells, which will also allow developing PET imaging to track T cell trafficking in real time in vivo. The parallel development of PET imaging capable of visualizing the tumor vasculature targets with the same scFv used in CIR will enable us to select the appropriate combinations of CIRs for personalized therapy and to monitor therapy. The impact of this approach could be transforming, given the power of tumor vascular disruption and its applicability across a wide range of targets shared by most common cancer types. The proposed approach can feasibly reach the clinic to deliver highly personalized cancer therapy of unparalleled power.