Targeting of natural killer-like T immunologic effector cells against leukemia and lymphoma cells by reverse antibody-dependent cellular cytotoxicity

Recently, highly efficient natural killer-like T immunologic effector cells called cytokine-induced killer (CIK) cells have been described. Most inter estingly, CIK cells have been shown to eradicate established human lymphoma cells in a severe combined immunodeficient (SCID) mouse xenograft model in vivo. The current study was aimed at increasing the sensitivity of leukemi a and lymphoma cells to CIK cells. In particular, the authors wanted to tar get CIK cells to leukemia and lymphoma cells via reverse antibody-dependent cellular cytotoxicity. Binding of an anti-CD3 monoclonal antibody to CIK c ell cultures derived from patients with lymphoma was shown using flow cytom etric analysis. For the target side, several B-cell lines were found to exp ress CD19 on the cell surface. There was an impressive increase in sensitiv ity to CTK-mediated lysis of various lymphoma and leukemia cell lines by pr eincubation of the targets with a monoclonal antibody against CD3. This inc rease could be partially blocked by preincubation with anti-CD16 (Fc recept or III) and anti-CD32 (Fe receptor II) antibodies. These data suggest that the increase in cytotoxic activity is caused by Fc receptor-mediated antibo dy binding. Cytotoxic activity could be further increased by adding an anti -CD28 antibody in addition to anti-CD3. Finally, there was a further increa se in sensitivity to CIK-mediated lysis of CD19(+) malignant cells using th e bispecific OKT3xHD37 antibody with specificity against CD3 and CD19. Inte restingly, preincubation of malignant cells with an anti-CD3 monoclonal ant ibody followed by addition of the bispecific OKT3xHD37 antibody led to a fu rther increase of cytotoxic sensitivity compared with the addition of the b ispecific antibody alone. In conclusion, these data suggest that cytotoxic activity of immunologic effector cells can be increased not only by using t he bispecific antibody OKT3xHD37 in vitro but also by preincubation of CD19 (+) leukemia and lymphoma cells with a monoclonal antibody against CD3. In addition, the immunostimulatory effect of the bispecific antibody OKT3xHD37 can be further increased by adding a monoclonal antibody against CD3.