Immunotherapy with anti-CD3 monoclonal antibodies and recombinant interleukin 2: Stimulation of molecular programs of cytotoxic killer cells and induction of tumor regression

Fumio Nakajima, Ashwani Khanna, Guoping Xu, Mila Lagman, Rudy Haschemeyer, Janet Mouradian, John C. Wang, Kurt H. Stenzel, Albert L. Rubin, Manikkam Suthanthiran

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21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7889-7893
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number17
DOIs
Publication statusPublished - 16 Aug 1994

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Keywords

  • T-cell signaling
  • antitumor efficacy
  • perforin

ASJC Scopus subject areas

  • General

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