Cancer therapy employing the tumour suppressing bacterium Caulobacter crescentus

使用肿瘤抑制细菌新月柄杆菌进行癌症治疗

• 批准号: 338552-2007
• 负责人: Smit, John
• 金额: $ 5.03万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Collaborative Health Research Projects
• 财政年份: 2007
• 资助国家: 加拿大
• 起止时间: 2007-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=366517
• 关键词: Cancer; therapy; employing; tumour; suppressing

We will exploit the flexible foreign protein display capabilities and the anti-tumor properties of the bacterium Caulobacter crescentus to develop a potent therapeutic cancer vaccine, hi mouse models we will examine the value of a) direct stimulation of immune system components by antibody-based targeting of cancer antigens in concert with other displayed immune stimulants and b) targeting tumors with Caulobacters displaying tumor-directed antibodies as well as cancer antigens and immune stimulants. Therapeutic cancer vaccine approaches offer significant advantages over chemotherapy, but finding the combination of antigen, delivery vehicle and adjuvanation to break anergy has proven difficult. Treatment using bacteria is a promising approach. One (BCG) is currently used for bladder cancer. Some bacteria exhibit anti-tumor properties but are pathogenic and propagate in the host and so are poorly suited for humans. This proposal offers an alternative. Caulobacter crescentus is a non-pathogen that does not replicate in mammals. It exhibits a crystalline protein surface (S) layer that is readily adapted to display large protein segments at high surface density. It also has strong anti-tumor properties. We will combine these observations to develop a therapeutic for cancer, requiring the microbial genetics efforts of a natural science lab to produce candidate therapeutics with the formulation expertise of a Pharmacy lab to evaluate efficacy and potency. Some specific Objectives: l)We will display single chain antibodies targeting receptors of dendritic cells (e.g., DEC-205) and simultaneously display cancer antigens (e.g., MUC1 and 5T4) and immune stimulants such as GM-CSF. This is done by expression of multiple modified S-layer protein genes. We can also use Protein G (IgG binding) display to "load" Caulobacters with targeting monoclonals. 2) We will also target vaccine formulations directly to tumors by use of antibodies to tumor markers, expecting to stimulate infiltrating immune cells. Several model systems will be tested including Lewis Lung Carcinoma and EMT-6 Murine Mammary tumor, the best results from prophylactic mode testing will also be evaluated in therapeutic mode.

我们将利用新月形杆菌灵活的外源蛋白展示能力和抗肿瘤特性来开发一种有效的治疗性癌症疫苗。在小鼠模型中，我们将检验a)通过基于抗体的靶向癌症抗原与其他展示的免疫刺激剂相结合直接刺激免疫系统组件的价值，以及b)通过展示肿瘤导向抗体以及癌症抗原和免疫刺激剂的Caulbacter靶向肿瘤的价值。与化疗相比，治疗性癌症疫苗方法具有显著的优势，但事实证明，找到抗原、递送载体和佐剂的组合来打破无效性是困难的。使用细菌治疗是一种很有前途的方法。其中一种(卡介苗)目前用于膀胱癌。一些细菌表现出抗肿瘤的特性，但它们是致病的，并在宿主中繁殖，因此不适合人类。这项提议提供了另一种选择。新月形杆菌是一种非病原体，不会在哺乳动物中复制。它显示出一层结晶的蛋白质表面(S)层，该层很容易适应以高表面密度显示大的蛋白质片段。它还具有很强的抗肿瘤特性。我们将结合这些观察结果来开发一种癌症治疗方法，要求自然科学实验室的微生物遗传学努力生产具有药房实验室配方专业知识的候选治疗药物，以评估疗效和效力。一些具体目标：L)我们将展示针对树突状细胞受体的单链抗体(如DEC-205)，同时展示癌症抗原(如MUC1和5T4)和免疫刺激物如GM-CSF。这是通过表达多个修饰的S层蛋白基因来完成的。我们也可以使用蛋白G(免疫球蛋白结合)展示来用靶向单克隆化来“装载”硫杆菌。2)我们还将通过使用肿瘤标志物抗体将疫苗配方直接靶向肿瘤，期望刺激渗入的免疫细胞。包括Lewis肺癌和EMT-6小鼠乳腺肿瘤在内的几个模型系统将进行测试，预防模式测试的最佳结果也将在治疗模式下进行评估。