IMMUNOTHERAPY WITH ANTI-CDS MONOCLONAL-ANTIBODIES AND RECOMBINANT INTERLEUKIN-2 - STIMULATION OF MOLECULAR PROGRAMS OF CYTOTOXIC KILLER-CELLS AND INDUCTION OF TUMOR-REGRESSION

Adoptive cellular immunotherapy, infusions of interleukin 2 (IL-2) in conjunction with in vitro-activated killer cells, has brought new hope to patients with cancer. The broad application of this strategy, howe ver, is constrained by the need for repeated leukapheresis and by the labor-intensive process of in r?itro activation of tells. Also, curren t protocols generally use nonphysiological and toxic concentrations of IL-2. Identification of an in vivo stimulant that renders T cells res ponsive to physiologic concentrations of IL-2 represents a potential i mprovement over existing approaches. We have determined whether in viv o administration of monoclonal antibodies (mAbs) directed at the T-cel l surface protein CD3 induces T-cell responsiveness to IL-2, stimulate s cytolytic molecular programs of natural killer cells and cytotoxic T cells, and induces tumor regression. These hypotheses were explored i n a murine hepatic MCA-102 fibrosarcoma model. We report that in vivo administration of anti-CD3 mAbs plus IL-2 results in intrahepatic expr ession of mRNA-encoding perforin, cytotoxic T-cell-specific serine est erase, and tumor necrosis factor cu. Anti-CD3 mAbs atone or IL-2 alone failed to induce or induced minimal expression of these molecular med iators of cytotoxicity. The anti-CD3 mAbs plus IL-2 regimen also resul ted in a significantly smaller number of hepatic metastases and a sign ificantly longer survival time of tumor-bearing mice, compared to trea tment with anti-CD3 mAbs alone or IL-2 alone. Our findings suggest tha t a regimen of anti-CD3 mAbs plus IL-2 is a more effective antitumor r egimen compared with anti-CD3 mAbs alone or IL-2 alone and advance an alternative immunotherapy strategy of potential value for the treatmen t of cancer in humans.