Cancer therapy employing the tumour suppressing bacterium Caulobacter crescentus

我们将利用新月柄杆菌的柔性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，我们将检查a）通过与其它展示的免疫刺激剂协同的基于抗体的癌抗原靶向直接刺激免疫系统组分和B）用展示肿瘤的柄杆菌靶向肿瘤的价值。定向抗体以及癌抗原和免疫刺激剂。治疗性癌症疫苗的方法提供了显着的优势，化疗，但发现抗原，运载工具和佐剂的组合，打破无反应性已被证明是困难的。使用细菌进行治疗是一种很有前途的方法。其中一种（BCG）目前用于膀胱癌。一些细菌表现出抗肿瘤特性，但具有致病性并在宿主中繁殖，因此不适合人类。这一提议提供了一种替代办法。新月柄杆菌是一种非病原体，不会在哺乳动物中复制。它具有晶体蛋白表面（S）层，易于适应以高表面密度显示大蛋白片段。它还具有很强的抗肿瘤特性。我们将联合收割机结合这些观察结果来开发一种癌症治疗方法，需要自然科学实验室的微生物遗传学努力，以生产具有药学实验室配方专业知识的候选治疗药物，以评估疗效和效力。1）我们将展示靶向树突状细胞受体的单链抗体（例如，DEC-205）并同时展示癌抗原（例如，MUC 1和5 T4）和免疫刺激剂如GM-CSF。这是通过表达多个修饰的S层蛋白基因来完成的。我们还可以使用蛋白G（IgG结合）展示来用靶向单克隆“加载”柄杆菌。2)我们还将通过使用针对肿瘤标志物的抗体将疫苗制剂直接靶向肿瘤，期望刺激浸润的免疫细胞。将测试几个模型系统，包括刘易斯肺癌和EMT-6小鼠乳腺肿瘤，还将在治疗模式下评价预防模式测试的最佳结果。

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.