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，在美国每年诊断出10，000例，患病率约为80，000例（2003年1月1日美国估计的28年有限持续时间患病率）（http：//seer.cancer.gov/）。 尽管对这种疾病的遗传学、生物化学和免疫学已经有了很多了解，但CLL仍然被认为是不可治愈的，需要开发改进的治疗策略。 与其他癌症一样，CLL细胞具有明显在这种疾病的发病机制或进展中起作用的遗传变化。 这种改变，沿着体细胞产生的免疫球蛋白基因的克隆表达，可以指导患者免疫系统靶向的“改变自身”蛋白的表达。 可以诱导针对自体白血病细胞的这种免疫应答的策略可能在治疗这种疾病中是有效的。 研究人员建议评估一种新的免疫基因治疗方式的临床前和临床活性，该免疫基因治疗通过使用编码嵌合（人-小鼠）CD 154分子（Ad-ISF 35）的复制缺陷型腺病毒载体的直接淋巴结内（结内）注射用CD 154（CD 40配体）转导白血病细胞介导。 与我们目前使用的需要对白血病/淋巴瘤细胞进行离体操作的方案相比，直接结内注射Ad-ISF 35可能被证明是一种有效且更便宜的策略来抑制癌细胞并诱导抗肿瘤反应。 从这笔赠款中获得的支持将促进1期临床数据，这对于在CLL中开发这种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.