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Immunotherapy of human tumors with T-cell-activating bispecific antibodies: stimulation of cytotoxic pathways in vivo.

Abstract
Bispecific monoclonal antibodies (Bi-mAbs) specific for a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes represent one of the most successful experimental strategies for the immunotherapy of cancer. We report that the in vivo administration of both alpha-CD3/CD30 and alpha-CD28/CD30 Bi-mAbs results in the specific activation of xenotransplanted, resting human T cells infiltrating the CD30-positive Hodgkin's tumor. Bi-mAb treatment resulted in enhanced expression of cytokines such as interleukin 1beta, interleukin 2, tumor necrosis factor type alpha, and activation markers including Ki-67, CD25, and CD45RO in tumor-infiltrating lymphocytes. This antigen-dependent, local T-cell stimulation led to the activation of the cytolytic machinery in T lymphocytes, determined by the up-regulation of mRNA-encoding perforin and the cytotoxic serine-esterases granzymes A and B. The Bi-mAb-induced generation of CTLs depended on the presence of the CD30 antigen and the combined application of both Bi-mAbs. Our findings suggest that the combined application of T-cell-activating Bi-mAbs is able to achieve a tumor site-specific activation of the T-cell cytolytic machinery in vivo. The fact that these cytotoxic cells do not home in tumor-associated antigen-negative tissue and do not enter circulation might explain our previous observations (C. Renner et al., Blood, 87: 2930-2937, 1996) of a high cure rate in preclinical models even at an advanced stage of disease.
AuthorsS Bauer, C Renner, J P Juwana, G Held, S Ohnesorge, K Gerlach, M Pfreundschuh
JournalCancer research (Cancer Res) Vol. 59 Issue 8 Pg. 1961-5 (Apr 15 1999) ISSN: 0008-5472 [Print] United States
PMID10213507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Bispecific
  • Cytokines
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Perforin
  • Serine Endopeptidases
Topics
  • Animals
  • Antibodies, Bispecific (therapeutic use)
  • Cytokines (metabolism)
  • Humans
  • Immunotherapy
  • Lymphocyte Activation
  • Membrane Glycoproteins (metabolism)
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Neoplasms, Experimental (immunology, therapy)
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Serine Endopeptidases (metabolism)
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 (biosynthesis)
  • Up-Regulation

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