THERAPEUTIC DNA VACCINES TO TREAT B CELL LYMPHOMA

我们提出了一系列实验，以评估提高正在开发的用于治疗低度非滤泡性淋巴瘤的质粒DNA肿瘤疫苗效力的方法。基于小鼠淋巴瘤模型系统的临床前肿瘤挑战研究和B细胞淋巴瘤患者的I/II期临床试验结果，我们已经证明了一种新型的双顺反子DNA载体，用于在注射到肌肉组织中时诱导抗独特型免疫反应，可以保护动物免受独特型肿瘤细胞的攻击，并能够在人类中产生免疫原性。最近的临床前研究表明，与独特型表达质粒相比，共注射第二个表达小鼠粒细胞-巨噬细胞集落刺激因子(mGM-CSF)的DNA质粒可提高动物的免疫原性和长期保护作用。本文介绍的一系列临床前实验旨在进一步提高这种多价质粒疫苗在小鼠和恒河猴身上的效力。我们预计这些实验将导致一种更有效的肿瘤疫苗，该疫苗将在第二次临床试验中在B细胞淋巴瘤患者身上进行测试。我们还预计，这种治疗性疫苗的成功将导致DNA疫苗用于治疗广泛的人类癌症。拟议的商业应用：目前还没有治疗人类低度滤泡性淋巴瘤的根治疗法。这项工作将推动一种新的肿瘤疫苗的开发，该疫苗在B细胞淋巴瘤患者中显示出希望。这种DNA疫苗旨在开发一种抗独特型免疫反应，从而抑制或消除肿瘤转移。DNA技术的发展，如基因的机器人克隆和表征，将使针对患者的疫苗的商业开发成为可能。

We propose a series of experiments which evaluate methods to increase potency of a plasmid DNA tumor vaccine being developed for the treatment of low grade non-follicular lymphoma. Based on the results of pre-clinical tumor challenge studies in a mouse lymphoma model system and a Phase I/II clinical trial in B-cell lymphoma patients, we have demonstrated that a novel bicistronic plasmid DNA vector, designed to elicit an anti-idiotype immune response when injected into muscle tissue, can protect animals from idiotype tumor cell challenge and can generate immunogenicity in humans. More recent pre-clinical studies indicate that co-injection of a second DNA plasmid, expressing the murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), increases immunogenicity and long-term protection in animals relative to the idiotype expression plasmid alone. The series of pre-clinical experiments presented here are designed to further increase the potency of this multivalant plasmid vaccine in mice and, in turn, rhesus monkeys. We anticipate that these experiments will lead to a more potent tumor vaccine which will be tested in B-cell lymphoma patients in a second clinical trial. We also anticipate that success of this therapeutic vaccine will lead to the use of DNA vaccines to treat a wide range of human cancers. PROPOSED COMMERCIAL APPLICATION: There is presently no curative therapy for the treatment of low-grade follicular lymphoma in humans. This work will advance the development of a novel tumor vaccine which is showing promise in B-cell lymphoma patients. This DNA vaccine is designed to develop an anti-idiotype immune response and thereby suppress or eliminate tumor metastases. Developments in DNA technologies, such as robotic cloning and characterization of genes, will make commercial development of patient- specific vaccines feasible.