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Development of Salmonella vaccines for cancer and viruses

开发针对癌症和病毒的沙门氏菌疫苗

基本信息

批准号：
10927887
负责人：
Olivia Steele-Mortimer
金额：
$ 42.93万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Salmonella are one of several different bacteria that have been shown to colonize solid tumors and are considered a leading contender for the development of bacterial-mediated anti-tumor therapy. Live recombinant attenuated Salmonella can be used to deliver proteins, DNA plasmids or other molecules directly to solid tumors or the tumor microenvironment. Salmonella can be delivered orally, are inexpensive to produce and can elicit both mucosal and systemic immune responses. Our goal is to engineer a safe attenuated strain to target solid tumors either alone or in combination with other treatments such as chemotherapy or immunotherapy. For the initial screening and identification of Tumor Colonization Factors of Salmonella Typhimurium and strain development, we are using a well-characterized melanoma model in which B16 melanoma cells are inoculated in the syngeneic C57BL6J mouse strain. Since C57BL6J mice are highly susceptible to infection with Salmonella Typhimurium, due in part to the lack of functional Nramp1/SLC11A1, we will also use Nramp1 reconstituted mice. Attenuated Salmonella Typhimurium strains will also be adapted to deliver chemotherapy or anti-tumor molecules (e.g. nanobodies) directly to tumors. Once promising Salmonella strains have been identified we will test additional in vivo models for metastasis in mice, including a model where human tumors can be xenografted into mice (in collaboration with Alana Welm).

沙门氏菌是已被证明可定植于实体瘤的几种不同细菌之一，被认为是细菌介导的抗肿瘤治疗发展的主要竞争者。活的重组减毒沙门氏菌可用于将蛋白质、DNA质粒或其他分子直接递送至实体瘤或肿瘤微环境。沙门氏菌可以口服，生产成本低，可以引起粘膜和全身免疫反应。我们的目标是设计一种安全的减毒菌株，单独或与其他治疗（如化疗或免疫治疗）联合靶向实体瘤。对于鼠伤寒沙门氏菌的肿瘤定植因子的初步筛选和鉴定以及菌株开发，我们使用了一种充分表征的黑色素瘤模型，其中B16黑色素瘤细胞接种在同基因C57 BL 6 J小鼠品系中。由于C57 BL 6 J小鼠对鼠伤寒沙门氏菌感染高度敏感，部分原因是缺乏功能性Nramp 1/SLC 11 A1，我们也将使用Nramp 1重建小鼠。减毒鼠伤寒沙门氏菌菌株也将适于将化疗或抗肿瘤分子（例如纳米抗体）直接递送至肿瘤。一旦确定了有希望的沙门氏菌菌株，我们将测试小鼠转移的其他体内模型，包括人类肿瘤可以异种移植到小鼠中的模型（与Alana Welm合作）。