CANCER IMMUNOTHERAPY WITH A LIVE RECOMBINANT VACCINE

在本申请中，申请人 希望探索单核细胞增生李斯特菌作为癌症的潜力， 有治疗作用的她在BALB/c小鼠中使用模型抗原系统 重组L.单核细胞增多症分泌肿瘤特异性 抗原不仅能保护机体免受肿瘤攻击， 在抗原特异性T细胞中肉眼可见的已建立肿瘤的消退 依赖细胞的方式。 免疫接种可以是口服或胃肠外，免疫似乎是长期的 在那只活了两个月后肿瘤已经消除的动物身上 没有再生长的迹象，并拒绝了100次的进一步挑战 相同肿瘤的致死剂量这种令人印象深刻的抗肿瘤药物 反应可能是由于这种兼性的不寻常的能力， 细胞内细菌逃避吞噬溶酶体并生存和生长 在细胞的细胞质中。L.单核细胞增多症， 因此，非常有效地针对II类和 I限制了抗原呈递的途径，导致强细胞 介导的免疫。因此，该细菌可能是理想的疫苗载体 用于加强TH 1、CD 4+和CD 8 + T细胞对肿瘤特异性免疫应答， 抗原作为癌症治疗剂。为了确定如何优化 L.的使用单核细胞作为人类癌症疫苗，申请人 将在三个具体目标中使用小鼠模型。具体目标1 将使用她已经建立并描述的模型， 初步研究包括L.单核细胞增多症 流感病毒核蛋白序列（NP）和转导有流感病毒核蛋白序列的肿瘤细胞 相同的NP基因，以建立最有效的相关性， 最安全的使用L单核细胞增多症作为癌症治疗。具体目标 2单核细胞增生李斯特菌诱导免疫力的能力， 表达内源性肿瘤抗原，P815的P1 A基因产物， 将确定BALB/c来源的肥大细胞瘤肿瘤。申请人 将使用具体目标1中得出的信息， 疫苗的有效性和一种新的L.单核细胞增生重组体， 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一种癌症治疗的自发性 将在转基因小鼠模型中测定小鼠体内的肿瘤， 其中SV 40 T抗原在probasin启动子的控制下 导致10周大的前列腺癌。SB 40 T抗原是一种 转基因小鼠中的真实自身抗原，因为该基因存在 在免疫系统成熟的过程中。这将允许 申请人确定重组L.单核细胞增多症， 分泌SV 40 T以打破宿主对肿瘤特异性抗原的耐受性。的 申请人的长期目标是充分探索相关的 癌症消退，由对肿瘤抗原的免疫应答诱导 由L交付。单核细胞增多症，在利用这种独特的 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.