Induction of an immune network cascade in cancer patients treated with monoclonal antibodies (ab1). I. May induction of ab1-reactive T cells and anti-anti-idiotypic antibodies (ab3) lead to tumor regression after mAb therapy?

The antitumor effector functions of unconjugated monoclonal antibodies in cancer therapy are complex. Direct cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity, complement-dependent cytolysis and apoptosis have been suggested. Induction of anti-idiotypic (ab2) and anti-anti-idiotypic (ab3) antibodies as well as T cell (T2 and T3 respectively) responses have also been proposed to be of clinical importance. In this study induction of an immune network cascade in patients with colorectal carcinoma, treated with mAb 17-1A (ab1) was assessed. All patients developed anti-idiotypic antibodies (ab2) of the IgG class after treatment with ab1 and four of nine patients showed induction of mouse Ig reactive T cells [a proliferative response to F(ab')2 fragments of ab1]. Patients with such a T cell response developed anti-anti-idiotypic antibodies (ab3), while those lacking the T cell reactivity failed to mount an ab3 response. Three of four patients with a T cell response achieved a tumor response to mAb therapy. Thus, all responding patients belonged to the group of individuals developing ab3. Induction of mAb(ab1)-reactive T cells as well as an immune network cascade might be important antitumor effector functions of mAb and should be considered in the future design of mAb-based therapy protocols in cancer patients.