GLIOMA SPECIFIC GENES IN BRAIN TUMOR IMMUNOTHERAPY

恶性胶质瘤的发病率和死亡率都很高，中位生存期不到两年。尽管在神经外科、放射和化疗方面取得了进展，但这些致命脑肿瘤患者的预后仍然很严峻。在目前正在研究的治疗恶性癌症的新方法中，没有一种在理论上像免疫疗法那样吸引人，因为它提供了潜在的高肿瘤特异性毒性。然而，尽管针对某些颅外肿瘤的免疫治疗试验取得了成功，但针对颅内肿瘤的免疫应答研究尚未取得令人鼓舞的结果。对此的一种解释是，早期脑肿瘤免疫治疗的尝试依赖于粗糙的肿瘤细胞制剂或一般的免疫刺激剂，缺乏特异性。最终，癌症免疫疗法作为恶性脑肿瘤的标准化治疗方法的成功取决于所提议的疫苗刺激特异性抗肿瘤（而不是抗脑）免疫反应的能力。理论上，这种反应可以通过鉴定肿瘤特异性基因产物（抗原）来实现，这些基因产物可以选择性地呈现给宿主免疫系统。直到鉴定出可操作的胶质瘤特异性抗原（存在于肿瘤组织中而不存在于正常大脑中），脑肿瘤免疫治疗的理论前景才会完全实现。因此，鉴定胶质肿瘤特异性抗原基因产物的挑战是选择合适的免疫攻击靶点的首要目标。为了实现这一目标，本提案旨在：1)使用已建立的和新的减法克隆方法鉴定假定的胶质瘤特异性基因；2)利用现代分子方法结合高通量基因阵列技术对这些基因进行表征；3)利用专业抗原呈递树突状细胞或单核增生李斯特菌载体，将体外发现的候选胶质瘤特异性基因产物转化为体内动物模型脑肿瘤免疫治疗的潜在治疗靶点，将抗原传递到宿主免疫反应的细胞臂上。希望这些研究目标和方法不仅能够为理解恶性脑肿瘤的分子生物学和发病机制提供一些新的见解，而且还可以填补我们现有的神经免疫学和基于免疫的神经肿瘤治疗知识的一些空白。

Malignant gliomas are responsible for significant morbidity and mortality, with a median survival of less than two years. Despite advances in neurosurgery, radiation, and chemotherapy, the prognosis of patients with these fatal brain tumors remains grim. Among the new treatments currently being investigated for malignant cancers, none is as theoretically appealing as immunotherapy because it offers the potential for high tumor-specific toxicity. However, despite some successful trials of immunotherapy against certain extracranial cancers, studies of immune responses against intracranial tumors have not yielded promising results. One explanation for this is that early attempts at brain tumor immunotherapy relied upon crude tumor cell preparations or general immune stimulants, which lacked specificity. Ultimately, the success of cancer immunotherapy as a standardized treatment for malignant brain tumors depends upon the ability of the proposed vaccine to stimulate a specific anti-tumor (and not anti-brain) immune response. Theoretically, such a response can optimally be achieved with the identification of tumor-specific gene products (antigens) that can be selectively presented to the host immune system. Not until the identification of operational glioma-specific antigens (present in tumor tissue but not in normal brain) will the theoretical promise of brain tumor immunotherapy be fully realized. Therefore, the challenge of identifying antigenic gene products specific to glial tumors is a crucial first objective in selecting appropriate targets for immune attack. To achieve this goal, this proposal aims to: 1) identify putative glioma-specific genes using established and novel subtractive cloning approaches; 2) characterize these genes using modern molecular methods coupled with high-throughput gene arraying technology; and 3) translate candidate glioma-specific gene products found in vitro into potential therapeutic targets for brain tumor immunotherapy in animal models in vivo by using professional antigen-presenting dendritic cells or the bacterial vector Listeria monocytogenes to deliver antigens to the cellular arm of the host immune response. Hopefully, these research aims and methods will not only provide some new insight into understanding the molecular biology and pathogenesis of malignant brain tumors, but also fill some of the gaps in our existing knowledge of neuro-immunology and immune-based therapies for neurological cancers.