GM-CSF Enhanced Colorectal Cancer Tumor Vaccine Program

描述(申请人提供)：在美国，结肠癌和直肠癌是新发病例和死亡的第三大常见部位。2002年估计有148,300例新病例和56,600例死亡。大多数情况下，癌症在确诊时已经转移，而最常见的远处转移部位是肝脏。一种很有希望的策略是利用患者自身免疫系统的抗肿瘤作用进行免疫治疗。肿瘤细胞与粒细胞-巨噬细胞集落刺激因子(GM-CSF)的旁分泌释放相结合，可以高效地产生强大的T细胞依赖的系统免疫，能够治愈预先建立的肿瘤负荷非常小的小鼠。这项建议的长期目标是建立一个基于GM-CSF肿瘤细胞疫苗的结直肠癌免疫治疗计划，并将新的治疗性免疫治疗方法从实验室转化到临床。 这项研究建议的具体目标是： 具体目标1：研究清除已建立的小鼠免疫反应的要素 GM-CSF增强型肿瘤细胞疫苗治疗肝转移的实验研究 将系统产生的免疫反应集中到肝脏的机制。 具体目标2：a)开发将肿瘤细胞与人类分离的标准操作规程 结直肠癌转移到肝脏，以便可以成功地分离、照射和储存用于疫苗制备。B)在临床上产生大量分泌GM-CSF的旁观者细胞。 具体目标3：进行I期临床试验，以研究疫苗的安全性和可行性 联合自体照射的肿瘤细胞抗结直肠癌的方法 肝转移瘤与分泌GM-CSF的旁观者细胞系相结合。

DESCRIPTION (provided by applicant): In the United States cancers of the colon and rectum are the third most common site of new cases and deaths. There were an estimated 148,300 new cases and 56,600 deaths from the disease in 2002. All too often, the cancer has metastasized by the time of diagnosis, and the most common site of distant metastasis is the liver. One promising strategy is immunotherapy that harnesses the antitumor effect of the patient's own immune system. Tumor cells combined with the paracrine release of granulocyte-macrophage colony stimulating factor (GM-CSF) are highly effective in generating potent T cell dependent systemic immunity capable of curing mice of very small burdens of pre-established tumors. The long-term objective of this proposal is to build an immunotherapy program against colorectal cancer based on GM-CSF tumor cell vaccines, and to translate novel therapeutic immunotherapeutic approaches from the laboratory to the clinics. The specific aims of this research proposal are: Specific Aim 1: To study the elements of the immune response of mice that eliminate established hepatic metastases after treatment with GM-CSF augmented tumor cell vaccines and to study mechanisms of focusing a systemically generated immune response into the liver. Specific Aim 2: A) To develop standard operating protocols to dissociate tumor cells from human colorectal cancer metastases to the liver so that they may be successfully isolated, irradiated, and stored for vaccine preparation. B) To produce a clinical lot of GM-CSF-secreting bystander cells. Specific Aim 3: To conduct a phase I clinical trial to study the safety and feasibility of a vaccine approach against colorectal cancer that combines autologous irradiated tumor cells isolated from hepatic metastases combined with a bystander cell line that secretes GM-CSF.