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.