Immunotherapy with anti-CD3 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, 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 alpha. 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.
Nakajima
F
F
Rogosin Institute, Department of Biochemistry, New York Hospital-Cornell Medical Center, NY 10021.
Khanna
A
A
Xu
G
G
Lagman
M
M
Haschemeyer
R
R
Mouradian
J
J
Wang
J C
JC
Stenzel
K H
KH
Rubin
A L
AL
Suthanthiran
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001483:Base Sequence; D017252:CD3 Complex / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D017931:DNA Primers; D005354:Fibrosarcoma / Q000276:immunology / Q000628:therapy*; D015870:Gene Expression / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008113:Liver Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D054353:Perforin; D016133:Polymerase Chain Reaction; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000627:therapeutic use; D012513:Sarcoma, Experimental / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D017931:DNA Primers; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D054353:Perforin