GM-CSF Enhanced Colorectal Cancer Tumor Vaccine Program

描述（由申请人提供）：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，56 600人死亡。 通常情况下，癌症在诊断时已经转移，最常见的远处转移部位是肝脏。 一种有希望的策略是利用患者自身免疫系统的抗肿瘤作用的免疫疗法。 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，在产生有效的T细胞依赖性全身免疫方面是高度有效的，所述免疫能够治愈具有非常小的预先建立的肿瘤负荷的小鼠。 该提案的长期目标是建立基于GM-CSF肿瘤细胞疫苗的结直肠癌免疫治疗方案，并将新的治疗性免疫方法从实验室转化为临床。 这项研究建议的具体目标是： 具体目标1：研究小鼠免疫应答的要素， 用GM-CSF增强的肿瘤细胞疫苗治疗肝转移后， 将全身产生的免疫反应集中到肝脏的机制。 具体目标2：A）开发标准操作方案以将肿瘤细胞从人 结肠直肠癌转移到肝脏，使得它们可以被成功地分离、辐照和储存用于疫苗制备。 B）产生临床批次的分泌GM-CSF的旁观者细胞。 具体目标3：开展一项I期临床试验，研究疫苗的安全性和可行性 一种治疗结直肠癌的方法， 与分泌GM-CSF的旁观者细胞系组合的肝转移。

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.