Therapeutic In Situ Vaccination for Human Lymphoma

描述（由申请人提供）：淋巴瘤提供了基于控制淋巴细胞存活和增殖的信号的治疗机会。由于Rituxan的出现，淋巴瘤的治疗已经发生了巨大的变化，Rituxan是一种被动给药的单克隆抗体，用于对抗普遍存在于b细胞上的CD20抗原。主动免疫疗法也在淋巴瘤（异体移植）中进行试验。患者接种肿瘤特异性B细胞受体表达的独特独特型疫苗可诱导抗肿瘤免疫应答。但三期试验未能显示PFS与单独的疫苗成分相比有益处。作为替代方案，我们已经开发了一种新颖和更实用的免疫治疗方法，我们称之为原位疫苗接种。我们将在淋巴瘤的单个部位杀死肿瘤细胞与直接在病灶内注射toll样受体9 （TLR9）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共刺激分子的上调。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。基于我们的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种新的疫苗概念。

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.