B7 1 GENE MODIFIED TUMOR CELL VACCINE FOR RENAL CELL CA

近年来，人们对开发治疗恶性肿瘤的免疫学方法越来越感兴趣，有很好的证据表明，肾细胞癌(RCC)的生长可以受到宿主免疫系统的调节。事实上，免疫调节细胞因子白介素2(IL-2)的使用被批准用于治疗这种疾病。这种方法的疗效仍然很低，目前还没有其他合理的传统疗法来治疗转移性肾癌。因此，有必要开发新的治疗策略。一种方法是开发自体肿瘤细胞疫苗，对其进行基因改造，使其具有更强的免疫原性。几个小组正在研究的一种这样的基因操作是永远表达B7-1，为肿瘤反应性T细胞提供共刺激。其基本原理是，为了产生细胞毒反应，T细胞需要两个信号：T细胞受体(TCR)与MHC上呈递的抗原肽的结合，以及CD28与B7-1的结合。由于肾癌细胞不表达B7-1，因此通过外源B7-1基因的强制表达可以使肿瘤细胞具有更强的免疫原性。我们最近完成了一项I期临床试验，患者正在接受经修饰表达B7-1的自体肿瘤细胞的治疗，B7-1具有肿瘤疫苗的功能。原发灶或转移灶均取自IV期肾细胞癌患者。肿瘤细胞适应于体外培养；感染由CMV启动子驱动的含有人B7-1基因的重组腺病毒载体；辐射；并储存在液氮中。根据剂量递增计划，等量的B7-1基因修饰的肿瘤细胞正在以不同的间隔作为疫苗接种给患者。患者还接受系统的IL-2，以达到为这种疾病提供公认的治疗以及扩大疫苗激活的肿瘤反应T细胞的双重目的。该疫苗的免疫原性和毒性正在12名患者身上进行评估。第一阶段试验将在四个月内(2000年1月)完成，收集和分析所有数据。一旦完成，我们建议使用同样的方法进行第二阶段试验，涉及30名患者。主要目标将是确定肿瘤应答率。治疗的免疫原性将通过对患者的外周血淋巴细胞进行ELISPOT分析以及在皮内注射自体未经修饰的肿瘤细胞48小时后进行DTH皮试活组织的免疫组织化学分析来评估。

There has been increasing interest in recent years in developing immunologic approaches to malignancies, and there is good evidence that the growth of renal cell carcinoma (RCC) can be modulated by the host's immune system. In fact the use of the immunomodulatory cytokine interleukin-2 (IL-2) is approved treatment for this disease. The efficacy of this approach remains low, and there is no other reasonable conventional therapy for patients with metastatic RCC. Therefore there is a need to develop novel treatment strategies. The development of autologous tumor cell vaccines, genetically modified to render them more immunogenic is one approach. One such genetic manipulation that is being studied by several groups is to everexpress B7-1 to provide costimulation to tumor-reactive T cells. The rationale for this is that in order to mount a cytotoxic response, T cells need two signals: the binding of the T cell receptor (TCR) to an antigenic peptide presented on MHC, and the binding of CD28 to B7-1. Since B7-1 is not normally expressed by RCC cells, the forced expression by transfection of an exogenous B7-1 gene could make the tumor cells more immunogenic. We recently completed accrual to a Phase I clinical trial where patients are being treated with autologous tumor cells modified to express B7-1 which functions as a tumor vaccine. Primary tumors or metastases were resected from patients with stage IV RCC. The tumor cells were adapted to in vitro culture; infected with a recombinant adenoviral vector containing the human B7-1 cDNA driven by the CMV promoter; radiated; and stored in liquid nitrogen. Aliquots of the B7-1 gene-modified tumor cells are being administered to the patients as a vaccine at varying intervals according to a dose escalation scheme. The patients also receive systemic IL-2 for the dual purpose of providing accepted therapy for this disease as well as expanding the tumor- reactive T cells activated by the vaccine. The immunogenicity and toxicity of the vaccine are in the process of being assessed in 12 patients. The Phase I trial will be completed with all of the data collected and analyzed in four months (January 2000). Once completed, we propose to conduct a Phase II trial involving 30 patients using this same approach. The primary objectives will be to determine tumor response rates. The immunogenicity of the treatment will be assessed by ELISPOT assays performed on the patients' peripheral blood lymphocytes and by immunohistochemical analysis of DTH skin test biopsies performed 48 hours after the intradermal injection of autologous, unmodified tumor cells.