CANCER IMMUNOTHERAPY WITH A LIVE RECOMBINANT VACCINE

描述：(申请人摘要)在本申请中，申请人 希望探索单核细胞增多性李斯特菌作为癌症的潜力 有治疗作用。她已经在BALB/c小鼠身上展示了使用模型抗原系统 一种重组的单核细胞增多性乳杆菌分泌一种肿瘤特异性的 抗原不仅可以预防肿瘤的攻击，而且还可以诱导 抗原特异性T细胞中肉眼可见肿瘤的消退 细胞依赖的方式。 免疫可以是口服或非肠道免疫，而且免疫时间似乎很长。 活在那两个月后肿瘤已经被消灭的动物 没有再生的迹象，拒绝100倍的进一步挑战 同一肿瘤的杀瘤剂量。这种令人印象深刻的抗肿瘤药物 这种反应很可能是由于这种兼职的特殊能力。 胞内细菌逃脱吞噬酶小体并生存和生长 在细胞质中。单核细胞增多性李斯特菌分泌的抗原， 因此，非常有效地针对II级和II级 我限制了抗原呈递的途径，导致了强大的细胞 中介免疫。因此，该细菌可能是理想的疫苗载体。 增强TH1、CD4+和CD8+T细胞对肿瘤的特异性反应 抗原作为治疗癌症的药物。为了确定如何优化 将L.单核细胞用作人类癌症疫苗，申请人 将在三个特定目标中使用鼠标模型。在特定的目标1她 将使用她已经建立的模型，并在 初步研究，由分泌的单核细胞增多性李斯特菌组成 流感病毒核蛋白序列(NP)与转导肿瘤细胞 相同的NP基因，以建立最有效和最 最安全地使用单核细胞增多性乳杆菌作为癌症治疗药物。以特定的目标 2单核细胞增多性李斯特氏菌诱导天然免疫的能力 表达内源性肿瘤抗原，P815的P1a基因产物 BALB/c来源的肥大细胞瘤，将被确定。申请人 将使用在特定目标1中获得的信息来最大化 疫苗的效力和一种新的单核细胞增多性李斯特菌重组 分泌这种抗原。最后，在具体目标3中，L. 单核细胞增多症作为自发产生的癌症治疗药物 体内小鼠的肿瘤将在转基因小鼠模型中确定 其中SV40T抗原受前盆地启动子控制 在10周大的时候会导致前列腺癌。SB40T抗原是一种 转基因小鼠的真实自身抗原，因为基因是存在的 在免疫系统成熟的过程中。这将允许 申请人确定重组单核细胞增多性李斯特菌的能力 分泌SV40T以打破宿主对肿瘤特异性抗原的耐受性。这个 申请者的长期目标是充分探索与之相关的 肿瘤抗原免疫反应诱导的癌症消退 由单核细胞增多性乳杆菌提供，在开发这一独特的 治疗人类癌症。

DESCRIPTION: (Applicant's Abstract) In this application the applicant wishes to explore the potential of Listeria Monocytogenes, as a cancer therapeutic. She has shown using a model antigen system in BALB/c mice that a recombinant L. monocytogenes that secretes a tumor specific antigen can not only protect against tumor challenge but can also induce regression of macroscopic established tumors in an antigen-specific T cell dependent manner. Immunization may be oral or parenteral and immunity appears to be long lived in that two months after the tumor has been eliminated animals show no signs of regrowth and reject a further challenge of 100 times the tumoricidal dose of the same tumor. This impressive anti-tumor response is probably due to the unusual ability of this facultative intracellular bacterium to escape the phagolysosome and live and grow in the cytoplasm of cells. Antigens secreted by L. monocytogenes, therefore, are very effectively targeted to both the class II and class I restricted pathways for antigen presentation resulting in strong cell mediated immunity. Thus this bacterium may be the ideal vaccine vector for boosting the TH1, CD4+ and CD8+ T cell response to tumor specific antigens as a cancer therapeutic. In order to determine how to optimize the use of L. monocytes as a cancer vaccine in humans, the applicant will use mouse models in three specific aims. In Specific Aim 1 she will use the model, which she already has established and described in the preliminary studies, consisting of L. monocytogenes that secretes the influenza nucleoprotein sequence (NP) and tumor cells transduced with the same NP gene, to establish the correlates for the most effective and safest use of L. monocytogenes as a cancer therapeutic. In Specific Aim 2 the ability of L.monocytogenes to induce immunity against a naturally expressed endogenous tumor antigen, the P1A gene product of the P815 BALB/c derived mastocytoma tumor, will be determined. The applicant will use the information derived in Specific Aim 1 to maximize the efficacy of the vaccine and a new L. monocytogenes recombinant that secretes this antigen. Finally, in Specific Aim 3, the ability of L. monocytogenes to act as a cancer therapeutic for spontaneously arising tumors in mice in vivo will be determined in a transgenic mouse model in which the SV40 T antigen is under the control of the probasin promotor resulting in prostate cancer by 10 weeks of age. SB40 T antigen is a true self antigen in the transgenic mouse since the gene is present during the maturation of the immune system. This will allow the applicant to determine the ability of a recombinant L. monocytogenes that secrets SV40T to break host tolerance to a tumor specific antigen. The applicant's long term goals are to fully explore the correlated for cancer regression, induced by the immune response to tumor antigens delivered by L. monocytogenes, prior to the exploitation of this unique therapeutic human cancer.