Immunotherapy with Anti-CD3 Monoclonal Antibodies and Recombinant Interleukin 2: Stimulation of Molecular Programs of Cytotoxic Killer Cells and Induction of Tumor Regression

• Published in: Proceedings of the National Academy of Sciences - PNAS 1994-08, Vol.91 (17), p.7889-7893
• Main Authors: Nakajima, Fumio, Khanna, Ashwani, Xu, Guoping, Lagman, Mila, Haschemeyer, Rudy, Mouradian, Janet, Wang, John C., Stenzel, Kurt H., Rubin, Albert L., Suthanthiran, Manikkam
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animals; Antibodies, Monoclonal - therapeutic use; Base Sequence; Cancer; CD3 Complex - immunology; Cytotoxicity, Immunologic - drug effects; DNA Primers; Fibrosarcoma - immunology; Fibrosarcoma - therapy; Gene Expression - drug effects; Immunity (Disease); Immunotherapy - methods; Interleukin-2 - therapeutic use; Interleukins; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Liver; Liver Neoplasms - immunology; Liver Neoplasms - prevention & control; Liver Neoplasms - secondary; Medical research; Membrane Glycoproteins - biosynthesis; Messenger RNA; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Natural killer cells; Perforin; Polymerase Chain Reaction; Pore Forming Cytotoxic Proteins; Recombinant Proteins - therapeutic use; RNA; RNA, Messenger - biosynthesis; Sarcoma, Experimental - immunology; Sarcoma, Experimental - therapy; Spleen; T lymphocytes; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.17.7889

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, however, is constrained by the need for repeated leukapheresis and by the labor-intensive process of in vitro activation of cells. Also, current protocols generally use nonphysiological and toxic concentrations of IL-2. Identification of an in vivo stimulant that renders T cells responsive to physiologic concentrations of IL-2 represents a potential improvement over existing approaches. We have determined whether in vivo administration of monoclonal antibodies (mAbs) directed at the T-cell surface protein CD3 induces T-cell responsiveness to IL-2, stimulates cytolytic molecular programs of natural killer cells and cytotoxic T cells, and induces tumor regression. These hypotheses were explored in a murine hepatic MCA-102 fibrosarcoma model. We report that in vivo administration of anti-CD3 mAbs plus IL-2 results in intrahepatic expression of mRNA-encoding perforin, cytotoxic T-cell-specific serine esterase, and tumor necrosis factor α. Anti-CD3 mAbs alone or IL-2 alone failed to induce or induced minimal expression of these molecular mediators of cytotoxicity. The anti-CD3 mAbs plus IL-2 regimen also resulted in a significantly smaller number of hepatic metastases and a significantly longer survival time of tumor-bearing mice, compared to treatment with anti-CD3 mAbs alone or IL-2 alone. Our findings suggest that a regimen of anti-CD3 mAbs plus IL-2 is a more effective antitumor regimen compared with anti-CD3 mAbs alone or IL-2 alone and advance an alternative immunotherapy strategy of potential value for the treatment of cancer in humans.