Tumor Therapy by Immune Recruitment with Bispecific Antibodies

Abstract

Many strategies for experimental immunotherapy of cancers aim at inducing and expanding tumor-specific cytotoxic T-lymphocytes. One of the most promising approaches uses bispecific monoclonal antibodies (Bi-MAbs) which are able to accumulate and activate human effector cells at the tumor site. Human resting peripheral NK- or T cells targeted by appropriate Bi-MAbs to tumor cells expressing a tumor-associated antigen display multiple signs of activation including proliferation, cytokine secretion, upregulation of cytotoxic peptides and enzymes and induce an efficient tumor cell lysis in vivo. Moreover, tumor-bearing SCID which were treated by effector cell-triggering Bi-MAbs and human peripheral blood lymphocytes had complete regressions of established tumors and most or all animals were cured by human NK-cell or T-cell cytotoxicity, respectively. Local tumor site-specific activation of T-cells was demonstrated, and enhanced granzyme and perforin expression together with the results of inhibition experiments suggest both mechanisms as the major contributors to the cytolytic machinery of Bi-MAb-mediated T-cell cytotoxicity in vivo. The encouraging results of this approach, which is able to cure animals with even advanced disseminated tumors, together with the local site-specific effector cell activation, which suggests minimal side effects, warrant the clinical evaluation of this Bi-MAb approach. As lymphocytes from tumor patients can be adequately activated by the respective Bi-MAbs, the clinical application of Bi-MAbs promises to become a safe, efficient and simple approach which should be readily applicable to the treatment of human malignancies that cannot be cured by standard regimens.