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Without Prior Stimulation, Tumor-associated Lymphocytes from Malignant Effusions Lyse Autologous Tumor Cells in the Presence of Bispecific Antibody HEA125xOKT3¹

Department of Molecular Immunology, German Cancer Research Center [G. S., G. M.], and Department of Obstetrics and Gynecology, University of Heidelberg [B. G., D. W.], 69120 Heidelberg, Germany

Women suffering from advanced stage ovarian or mammary carcinoma frequently develop malignant ascites or pleural effusions consisting of tumor cells and tumor-associated lymphocytes (TALs). Locoregional immunotherapy with bispecific antibodies (bsAbs), which retarget T cells to tumor cells and induce their lysis, has been applied as an adjuvant treatment in the late stage of the disease. Until now, most of these therapies use peripheral blood mononuclear cells (PBMCs) as effector cells that have been stimulated and expanded ex vivo and loaded with bsAb before reinjection. Here we investigated whether TALs derived from malignant ascites or pleural effusions can be used as bsAb-guided effector cells without prior in vitro stimulation.

For this we established a bsAb, HEA125xOKT3, which recognizes the epithelial antigen Egp34 on carcinoma cells and the CD3 molecule on T cells. BsAb HEA125xOKT3 induced lysis of various Egp34-expressing carcinoma lines by stimulated PBMCs. Optimal cytotoxicity was achieved at a bsAb concentration of 1 µg/ml. In three ovarian and two mammary carcinoma patients, we demonstrated efficient lytic activity of lymphocytes, isolated from malignant ascites or pleural effusion. Without prior stimulation, they lysed autologous tumor cells in the presence of bsAb HEA125xOKT3, indicating that they are already activated. Along this line, a subset of CD4⁺ and CD8⁺ unstimulated TALs expressed the early activation marker CD69. They are, however, negative for CD95, and only a small subpopulation of CD4⁺ TALs expresses CD25. OKT3/interleukin 2 stimulation of TALs increased the expression of activation markers on the CD4⁺ and CD8⁺ T-cell compartment. The activation markers CD69, CD25, CD95, and DR molecules are up-regulated on both T-cell types. However, lysis of autologous tumor cells by stimulated TALs is not significantly enhanced compared with unstimulated TALs. Our results may offer a novel and promising concept of adjuvant immunotherapy for ovarian and mammary carcinoma patients. Preactivation and expansion of PBMCs can be circumvented by exploring the cytotoxic capacity of unstimulated TALs in the presence of bsAbs in a locoregional therapeutic approach.

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