Phase I, Open-Label Dose-Escalation

描述(由申请人提供)： 慢性淋巴细胞白血病是西方社会最常见的成人白血病，在美国每年有10,000例确诊病例，患病率约为80,000例(美国估计2003年1月1日的28年有限流行率)(http://seer.cancer.gov/).虽然关于这种疾病的遗传学、生化和免疫学已经了解了很多，但CLL仍然被认为是无法治愈的，需要改进治疗策略的发展。与其他癌症一样，CLL细胞存在基因变化，显然在这种疾病的发病机制或进展中发挥了作用。这种改变，连同体细胞产生的免疫球蛋白基因的克隆表达，可能会指导患者免疫系统可能针对的“改变的自我”蛋白的表达。能够诱导针对自体白血病细胞的免疫反应的策略可能在治疗这种疾病方面是有效的。研究人员建议评估一种新的免疫基因治疗方法的临床前和临床活性，该方法通过转导带有CD154(CD40配体)的白血病细胞，通过直接淋巴结内(结内)注射编码嵌合(人-鼠)CD154分子的复制缺陷型腺病毒载体(Ad-ISF35)。与我们目前使用的需要体外操纵白血病/淋巴瘤细胞的方案相比，直接结内注射Ad-ISF35可能被证明是一种有效且更便宜的转导癌细胞和诱导抗肿瘤反应的策略。 从这笔赠款中获得的支持将促进第一阶段临床数据的提供，这些数据对于开发CLL的这一治疗策略及其对其他类型癌症的潜在应用至关重要。

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia is the most common adult leukemia in Western societies with 10,000 cases diagnosed in the United States every year and a prevalence of approximately 80,000 cases (US Estimated 28-Year Limited-Duration Prevalence on 1/1/2003) (http://seer.cancer.gov/). Although much has been learned about the genetics, biochemistry and immunology of this disease, CLL still is considered incurable, mandating development of improved treatment strategies. Like other cancers, CLL cells harbor genetic changes that apparently play a role in the pathogenesis or progression of this disease. Such alterations, along with the clonal expression of somatically generated immunoglobulin genes, may direct expression of "altered-self" proteins that could be targeted by the patient's immune system. Strategies that can induce such immune responses against autologous leukemia cells may be effective in the treatment of this disease. The investigators propose to evaluate the pre-clinical and clinical activity of a new modality of immuno-gene therapy mediated by transduction of leukemia cells with CD154 (CD40 Ligand) using direct intra-lymph node (intranodal) injection of a replication-defective adenovirus vector that encodes a chimeric (human-mouse) CD154 molecule (Ad-ISF35). Direct intranodal injection of Ad-ISF35 may prove to be an effective and less expensive strategy to transduce cancer cells and induce anti-tumor responses compared with the current protocols that we are using in which ex-vivo manipulation of the leukemia/ lymphoma cells is required. The support obtained from this grant will facilitate Phase 1 clinical data that is essential for the development of this therapeutic strategy in CLL and its potential applications to other types of cancer.