INDUCTION OF AN IMMUNE NETWORK CASCADE IN CANCER-PATIENTS TREATED WITH MONOCLONAL-ANTIBODIES (AB(1)) .2. IS INDUCTION OF ANTIIDIOTYPE REACTIVE T-CELLS (T-3) OF IMPORTANCE FOR TUMOR RESPONSE TO MAB THERAPY

The antitumor effector functions of unconjugated monoclonal antibodies (mAb) in cancer therapy are not fully understood. Direct cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity, complement-dependent cytolysis and apoptosis have been suggested. Induction of anti-idiotypic (ab(2)) and anti-anti-idiotypic (ab(3)) antibodies as well as the corresponding T cells (T-2 and T-3) has also been proposed to be of therapeutic significance. In this study induction of an immune network cascade in ten patients with colorectal carcinoma, treated with mAb 17-1A (ab(1)) was assessed. After treatment, all ten patients had anti-idiotypic antibodies and anti-anti-idiotypic antibodies with ab(1)-like binding specificity while only five of ten patients had T cells corresponding to ab(3) (T-3) as assessed by a proliferation assay (DNA synthesis), and an assay of interferon gamma production (ELISPOT) (Enzyme-Linked immune SPOT) in vitro or by a delayed-type hypersensitivity reaction in vivo. Purified T cells from four of the five patients with a positive T-3 test responded with DNA synthesis after stimulation using human anti-mAb 17-1A anti-idiotypic monoclonal antibodies. These four patients had a clinical response showing a tumor reduction after therapy, while all six patients lacking a proliferative response failed to show tumor regression. Induction of a cell-mediated immune network cascade might accordingly be an important antitumor effector function of mAb and should be considered in the future design of mAb-based therapy protocols in cancer patients.