Therapeutic In Situ Vaccination for Human Lymphoma

描述(申请人提供)：淋巴瘤提供了一种基于控制淋巴细胞存活和增殖的信号的治疗机会。Rituxan的出现极大地改变了淋巴瘤的治疗方法，Rituxan是一种被动注射的抗CD20抗原的单抗，普遍存在于B细胞上。主动免疫疗法也在淋巴瘤(同种异体移植)中进行测试。给患者接种肿瘤特异性B细胞受体表达的独特型疫苗可以诱导抗肿瘤免疫反应。但第三阶段试验未能显示与单独使用疫苗成分相比，PFS有好处。作为替代方案，我们开发了一种新的、更实用的免疫治疗方法，我们称之为原位疫苗接种。我们将淋巴瘤单个部位的肿瘤细胞杀伤与肿瘤内直接注射Toll样受体9(TLR9)的配体相结合，以诱导肿瘤细胞和浸润性宿主抗原提呈细胞上协同刺激分子的上调。这导致宿主的T细胞免疫反应，可以消除动物模型中的转移性疾病。根据我们临床前动物模型的结果，我们假设通过使用针对CTLA4的抗体，我们可以进一步增强这种治疗性免疫反应。在这里，我们建议在淋巴瘤患者中测试这一新的疫苗概念。

DESCRIPTION (provided by applicant): Lymphoma affords an opportunity for therapy based on the signals that control lymphocyte survival and proliferation. The therapy of lymphoma has been dramatically changed by the advent of Rituxan, a passively administered monoclonal antibody against CD20 antigen ubiquitous on B-cells. Active immunotherapy is also being tested in lymphoma (allogeneic transplantation). Vaccination of patients against the unique idiotype expressed by the tumor specific B cell receptor can induce anti-tumor immune responses. But Phase III trials failed to show a benefit in PFS compared to the vaccine ingredients alone. As an alternative we have developed a novel and more practical immunotherapy approach that we call in situ vaccination. We combine tumor cell killing at a single site of lymphoma with direct intralesional injection of a ligand for toll like receptor 9 (TLR9) to induce the up-regulation of costimulatory molecules on the tumor cells and on the infiltrating host antigen presenting cells. This results in a T cell immune response by the host that can eliminate metastatic disease in animal models. Based on the results of our preclinical animal model, we hypothesize that by using an antibody against CTLA4, we can further enhance this therapeutic immune response. Here we propose to test this novel vaccine concept in patients with lymphoma.