ADMIN OF AUTOLOGOUS DENDRITIC CELLS ACTIVATED BY GM-CSF & IL-4 AS TUMOR VACCINE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。今年，膀胱癌将导致12000人死亡。近30-35%的患者患有肌肉侵袭性疾病。标准的治疗方法是根治性膀胱切除术，但40%-50%的患者会复发。在这种情况下，新辅助化疗没有明显的生存益处，因此新的治疗策略是必要的。树突状细胞(DC)是一种高效的抗原提呈细胞，能刺激一次和二次免疫反应。临床前的体外和动物实验数据表明，可以从外周血中获取丰富的DC，并在细胞因子存在的情况下进行培养，以增强DC的功能。使用肿瘤裂解物或抗原肽培养，肿瘤特异性呈现可以在动物和人类中导致增强的T细胞反应和抗肿瘤效果。在各种晚期成人和儿童肿瘤中正在进行的I期试验的数据也表明，皮内接种树突状细胞疫苗的毒性最小。该方案的假设是，DC可以通过瘤内注射暴露于肿瘤抗原而将膀胱癌特异性抗原递送给免疫系统。这项I期试验将概述瘤内注射激活的和KLH脉冲的自体树突状细胞的安全性。在这方面，将采用树突状细胞给药的剂量递增。我们将研究在门诊环境下使用柔性膀胱镜进行目测给药的膀胱肿瘤内细胞注射的可行性。此外，将通过免疫学和免疫组织化学分析来探索与DC疫苗相关的免疫学和抗肿瘤反应。本研究的具体目的包括：1.确定局部晚期膀胱癌患者每周瘤内注射自体、活化的、KLH致敏的树突状细胞疫苗的安全性。2.概述DC连续瘤内注射的可行性。3.评价活化KLH冲击DC治疗后的免疫学反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bladder cancer will kill 12,000 people this year. Nearly 30-35% of patients present with muscle invasive disease. The standard therapy is radical cystectomy, however, 40-50% of patients will recur. Neoadjuvant chemotherapy offers no clear survival benefit in this setting, so novel treatment strategies are necessary. Dendritic cells (DC) are highly potent antigen presenting cells that stimulate primary and secondary immune responses. Preclinical in vitro and animal data have shown that enriched DC can be harvested from peripheral blood and cultured in the presence of cytokines to enhance DC function. Using tumor lysates or antigen peptide culture, tumor-specific presentation can result in a heightened T-cell response and an antitumor effect in animals and in humans. Data from ongoing Phase I trials in a variety of advanced adult and pediatric tumors has also demonstrated a minimal observable toxicity with the administration of intradermal dendritic cell vaccination. The hypothesis of this proposal is that DC can be utilized to present bladder tumor specific antigens to the immune system through exposure to tumor antigens using intratumoral injection. This Phase I trial will outline the safety profile of intratumoral injection of activated and KLH-pulsed autologous dendritic cells. In this regard, a dose escalation of dendritic cell administration will be employed. We will study the feasibility of intravesical intratumoral cell injection using flexible cystoscopy for visually directed administration in the outpatient setting. Further, immunologic and antitumor responses related to DC vaccination will be explored through immunologic and immunohistochemical analyses. The specific aims of this study include the following: 1. To determine the safety of weekly intratumoral administration of autologous, activated, KLH-pulsed dendritic cell vaccines in locally advanced bladder cancer patients. 2. To outline the feasibility of serial intratumoral DC injections. 3. To evaluate the immunologic response to activated KLH-pulsed DC therapy.