Transformative personalized vascular disrupting cancer immunotherapy

描述（由申请人提供）：虽然大多数抗癌治疗工作旨在直接靶向肿瘤细胞，但靶向肿瘤血管系统（TV）有很强的理由。用于治疗的血管特异性工具的开发受到以下因素的阻碍：（a）靶点的缺乏，（B）缺乏具有最佳亲和力和特异性的试剂，以及（c）由于中和抗体的快速清除和/或产生而导致的其短暂作用。该提案旨在解决目前癌症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新的强大和个性化的方法。T细胞将用慢病毒载体工程化以表达嵌合免疫受体（CIR），融合分子包含细胞外单链可变片段（scFv）抗体结构域和胞质内CD 3、CD 28和4-1BB信号传导结构域，用于稳健的T细胞活化。患者来源的淋巴细胞将被基因重编程以识别肿瘤血管，被肿瘤血管激活并特异性破坏肿瘤血管。这种方法将细胞毒性T细胞的敏感性和能力与scFv的特异性相结合，并将在肿瘤血管系统上释放急性移植排斥的能力。除了特异性和安全性外，这种方法还具有耐用性和长期记忆性。已经针对肿瘤血管表面蛋白TEM 1、TEM 7 R和PSMA开发的CIR将用于验证该方法，而针对PI实验室和其他人鉴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CIR的组合，用于最常见和最难治疗的肿瘤的个性化血管免疫治疗。通过需要同时识别两种不同的肿瘤血管抗原以激活T细胞，通过在两种不同的CIR中将CD 3与CD 28/4-1BB结构域物理分离，每种CIR识别不同的肿瘤血管靶标，将安全性最大化。两种靶标在正常组织中共表达的可能性可以忽略不计，从而最大化治疗窗口。将自杀基因整合到工程化T细胞中将提供额外的安全性，这也将允许开发PET成像以在体内真实的时间跟踪T细胞运输。能够用CIR中使用的相同scFv可视化肿瘤脉管系统靶标的PET成像的平行开发将使我们能够选择用于个性化治疗的CIR的适当组合并监测治疗。这种方法的影响可能会改变，考虑到肿瘤血管破坏的力量及其在大多数常见癌症类型所共有的广泛靶点上的适用性。所提出的方法可以切实可行地到达诊所，以提供无与伦比的高度个性化的癌症治疗。

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.