Transformative personalized vascular disrupting cancer immunotherapy

描述(申请人提供)：虽然大多数抗癌治疗的目的是直接针对肿瘤细胞，但有一个强大的理由，以肿瘤血管(TV)为目标。血管特异性治疗工具的开发受到以下因素的阻碍：(A)靶标缺乏，(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/或发展中和抗体，其作用时间短暂。这一建议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新的、强大的、个性化的自体过继血管干扰性淋巴细胞免疫治疗方法。T细胞将与慢病毒载体一起表达嵌合免疫受体(CIRs)，融合分子包括细胞外单链可变区(ScFv)抗体结构域和胞浆内CD3、CD28和4-1BB信号域，以实现强大的T细胞激活。患者来源的淋巴细胞将被基因重新编程，以识别肿瘤血管，被肿瘤血管激活并具体地说破坏肿瘤血管。这种方法结合了细胞毒性T细胞的敏感性和能力以及单链抗体的特异性，将释放出急性移植排斥反应对肿瘤血管的作用。除了特异性和安全性，这种方法还提供了耐用性和长期记忆力。已经针对肿瘤血管表面蛋白TEM1、TEM7R和PSMA开发的CIRS将用于验证该方法，而针对PI实验室和其他实验室确定的其他肿瘤血管靶点的单链抗体将被开发出来。该项目的成功完成将为临床带来模块化CIRS的组合，用于对最常见和最顽固的肿瘤进行个性化血管免疫治疗。通过要求同时识别两个不同的肿瘤血管抗原来激活T细胞，通过物理地将CD3从两个不同的CIR中的CD28/4-1BB结构域分离出来，每个CIR识别不同的肿瘤血管靶点，将安全性最大化。这两个靶点在正常组织中共表达的可能性微乎其微，从而最大化了治疗窗口。通过在工程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。与CIR中使用的相同单链抗体的肿瘤血管靶点的PET成像的平行发展将使我们能够选择合适的CIR组合用于个性化治疗和监测治疗。考虑到肿瘤血管破坏的力量以及它对大多数常见癌症类型共享的广泛靶点的适用性，这种方法的影响可能是转变的。所提出的方法可以可行地到达临床，提供具有无与伦比的力量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.