GM-CSF Enhanced Colorectal Cancer Tumor Vaccine Program

描述（由申请人提供）：在美国，结肠癌和直肠癌是第三大最常见的新病例和死亡部位。2002年估计有148 300个新病例和56 600人死于该病。通常，癌症在诊断时已经转移，最常见的远处转移部位是肝脏。一种很有前景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。肿瘤细胞与旁分泌释放的粒细胞-巨噬细胞集落刺激因子（GM-CSF）结合，在产生强有力的T细胞依赖性全身免疫方面非常有效，能够治愈小鼠非常小的预先建立的肿瘤负担。本课题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治疗方法从实验室转化为临床。

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.