ANTIIDIOTYPE VACCINE THERAPY OF HUMAN COLORECTAL CANCER

点击翻译按钮获取中文摘要

We have generated a murine monoclonal anti-idiotype ( antibody, 3Hl, that is the internal image of the carcinoembryonic antigen (CEA). We have demonstrated that patients with advanced metastatic colorectal cancer (CRC) and patients with high risk CRC in the post-surgical adjuvant setting generate an active immune response against CEA following an adequate number of immunizations with the Chl anti-Id adsorbed to aluminum hydroxide. We demonstrated a predominantly IgG polyclonal humoral immune response with specific binding to purified CEA and CEA positive cells that mediated antibody-dependent cellular cytotoxicity. The vaccinated patients also demonstrated in vitro T cell proliferative responses in the presence of anti-Id 3Hl, CEA or synthetic peptides derived from 3H1 and CEA. While one of the patients had objective clinical response to 3Hl, several continue on vaccine therapy with stable disease from 12-36 months. Toxicity was limited to local reactions at the site of the injection with mild fevers. In this project, we will conduct clinical trials in which patients with Dukes B and C colorectal carcinoma will be treated with adjuvant 5FU and leucovorin and anti-Id 3Hl in combination with different immunologic adjuvants such as GS-21, GM-CSF or low-dose IL-2. The patients will be observed for immune responses and for clinical outcome. Animal models in C57BL/6 mice transplanted with the human CEA transfected murine colon cancer cell line MC38 will be used to develop more powerful methods of immunization utilizing the anti-Id 3Hl derivatives and to dissect the mechanisms of anti-tumor immunity. We will investigate a single chain Fv molecule (scFv) of 3Hl as an immunogen mixed with variety of adjuvants and cytokines. We will investigate the role of dendritic cell (DC) in developing tumor immunity after pulsing them with relevant anti-idiotypic reagents. In addition, adenoviral vectors (AdV) will be used to introduce 3H1-scFv or CEA into DC, which in turn will be tested for vaccine potential. We will also generate potentially therapeutic DC from leukapheresis products of CRC patients (some of them may be pretreated with 3H1 vaccine), and pulse them with the anti-Id 3Hl, CEA or relevant peptides or transduce them with Adv expressing these genes and examine their antigen presenting and T cell stimulatory function or T cell cytolytic function in vitro. These studies will be a prelude to clinical trials for CRC patients with autologous DC based anti-Id vaccine and scFv.