EACR-12: 12th Biennial Meeting of the European Association for Cancer Research. April 4-7, 1993, Brussels, Belgium, 1993.. Unique Identifier : AIDSLINE ICDB/94697527 Thielemans K; Lab. of Physiology-Immunology, Vrije Universiteit Brussel, B-1090; Brussels, Belgium
Abstract:
The idea to target T lymphocytes toward tumor cells has been tested extensively and successfully by many laboratories. Our laboratory has evaluated this attractive approach in vivo. We have developed bispecific antibodies by hybrid-hybridoma technique, with dual specificity: the murine CD3 complex and the idiotype (tumor specific antigen) of the surface expressed IgM on two murine B-cell lymphomas. Since the primary goal of our experiments was to evaluate the therapeutic potential of this approach in vivo, we have invested great efforts in the generation of proper control reagents. Using the aggressive 38C13 lymphoma of C3H origin, we showed that bispecific antibodies could cure a significant number of tumor-bearing animals. Animals with even a lower tumor burden were not protected with any of the control antibodies (bi- or univalent class-matched anti-idiotype mAb, bi- or univalent anti-CD3 mAb). Tumor-bearing C3H/HeJ mice (not able to perform FcR-dependent ADCC) could also be successfully treated. Animals in which we had induced allo-sensitized effector T cells showed a much higher cure rate in comparison with the experiments in untreated animals. Further evidence that the therapeutic effect was T-cell-mediated and dependent on the bridge formation between tumor cells and T cells, was obtained by using a tumor-antigen negative variant of the 38C13 tumor line and by using a mixture of a T-cell binding/nontumor-cell binding antibody plus a tumor-cell binding/nonT-cell binding antibody. Similar results were obtained with the BCL1 lymphoma model in BALB/c mice. The efficacy of the bispecific antibodies was dependent on both tumor load and dose. Repeated injections of bispecific antibodies could cure more mice than a single injection. Treatment of tumor-bearing mice in which either CD4+, CD8+ or both subsets had been depleted, clearly indicated the T-cell-mediated effect and the contribution of both subsets to the tumor eradicating mechanism. Taken together, our data indicate that it is indeed possible to recruit and focus T cells against a given target in vivo. Ongoing experiments explore the T-cell-mediated mechanism and the potential improvement of our results by combining two bispecific antibodies which will activate the T cells at the tumor site via CD3 and CD28.
Keywords: Animal Antibodies/*ADMINISTRATION & DOSAGE CD4-CD8 Ratio *Immunotherapy Lymphoma/IMMUNOLOGY/*THERAPY Mice Mice, Inbred BALB C Mice, Inbred C3H T-Lymphocytes/IMMUNOLOGY ABSTRACT 941230
M94C4337
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