Maria A. Garrido

Targeted cytotoxic cells as a novel form of cancer immunotherapy.

Cellular cytotoxicity is mediated by receptors on the surfaces of cytotoxic cells (lysis promoting receptors) which are specific for cell surface components on target cells. Such receptors mediate the formation of conjugates between effector and target cells, and transduce signals which cause the cytotoxic ceils to deliver “lethal hits” to the bound target cells. Subsequently, the two cells separate, leaving moribund target cells and cytotoxic cells which are free to lyse other target cells (Martz, 1977; Henkart, 1985). This process can be artificially manipulated by using heterocross-linked antibodies which contain an antibody against the lysis promoting receptor linked to an antibody against a surface component on a perspective target cell (Karpovsky et al., 1984; Staerz et al., 1985; Perez et al., 1985; Segal and Wunderlich, 1987). Such antibody heteroconjugates can bind a target cell which would not normally be lysed to the lysis promoting receptor on the cytotoxic cell and signal the cytotoxic cell to deliver a lethal hit. Thus, heteroconjugates can change target specificities of cytotoxic cells. Because monoclonal antibodies (MAb) against pathogenic cells could be incorporated into heteroconjugates, they could have important medical applications. In particular, the authors and others (Perez ef al., 1986; Titus et al., 1987a; Jung et ul., 1986; Lanzavecchia and Scheidegger, 1987; Staerz and Bevan, 1986; Liu et al., 1985) have been interested in using heteroconjugates containing anti-tumor antibodies to direct cellular cytotoxic responses against human cancers. Several classes of cytotoxic cells have been targeted using heteroconjugated antibodies. Antibodies against components of the T-cell receptor complex (either T, or CD3) (Perez et ul., 1985; Staerz et al., 1985) or against CD2 (in man) (Siliciano et al., 1985) and Ly6 (in mouse) (Leo et al., 1987) redirect the specificity of cytotoxic T-cells. Other types of cells have been targeted through PC, receptors: human K-cells through the Fc,RIII (Titus et al., 1987b), also known as CD16, and monocytes and neutrophils through Fc,RI and II (Shen et al., 1986, 1987; Graziano and Fanger. 1987). Lysis mediated by targeted Tand K-cells is enhanced by incubating the effector cells with IL-2 (Titus er al., 1987b), whereas killing by monocytes and neutrophils is boosted by interferon-y (Graziano and Fanger, 1987). In this paper we will summarize our recent studies using targeted Tand K-cells to kill tumor cells, both in the and in vim.

Bispecific antibodies and retargeted cellular cytotoxicity: novel approaches to cancer therapy

SummaryWe have used a relatively new technology to increase the number of human lymphocytes that will react with human ovarian carcinoma cells. This technology, often called “retargeting of the immune system,” can temporarity redirect the activity of immune cells that were originally committed to react with foreign substances other than cancer cells. In the example presented here, the antitumor effects of retargeted human T lymphocytes, collected from normal donors, were tested in immunodeficient mice with a human ovarian carcinoma line growing intraperitoneally. We retargeted T cells in vitro with a bispecific antibody that reacted with the T cell receptor complex and with a cell-surface antigen expressed by the ovarian carcinoma cells. Retargeted lymphocytes, injected intraperitoneally into mice 4 days after intraperitoneal injection of the tumor cells, impeded tumor growth and doubled the host survival time. These findings provide support for the concept that treatment of ovarian cancer patients with retargeted T cells could prove beneficial.