Bispecific antibody-mediated immunotherapy of the BCL1 lymphoma: increased efficacy with multiple injections and CD28-induced costimulation.

Abstract

The BCL1 lymphoma in Balb/c mice can be successfully treated with bispecific (anti-CD3 x anti-idiotype) antibodies (BSABs). In these experiments, animals were injected intraperitoneally (IP) with 5 x 10(3) tumor cells (day 0) and treated with one single intravenous (IV) injection of 5 micrograms BSAB (day 9). Because cross-linking of the CD3 complex is not in itself sufficient to activate resting T cells, the therapeutic success was mainly based on the progressive retargeting of the relatively small cytotoxic T-lymphocyte effector cell pool already in existence in vivo. For this reason, the therapy lost its effectiveness at higher tumor loads. Two possibilities were explored to treat mice with a higher tumor load (10(5) tumor cells). First multiple injections of BSABs were used, but a dose-related monovalent anti-CD3 immunosuppression was induced. This approach was only beneficial when the immune system was able to recover from the previous injection of BSAB. As a second approach, CD28 costimulation together with BSABs were used in an attempt to activate resting T cells, ultimately enlarging the effector T-cell pool. However, we were repeatedly unsuccessful in attempts to improve our in vivo results using young, naive animals in which the majority of T cells are of the naive phenotype. Only when animals were primed to induce the memory T-cell type was a significantly better outcome observed, and then only with multiple injections of BSABs and anti-CD28 monoclonal antibodies (MoAbs), rather than with BSAB or anti-CD28 MoAb alone. These results suggest that this combination was able to activate memory and effector T cells and to focus them on the tumor, but was unable to activate naive T cells fully. The in vivo potency of the BSAB and CD28 costimulation was shown by the fact that one-tenth of the quantity of BSAB was required to cure animals with 20 times the tumor load.

• Authors: C Demanet, J Brissinck, J De Jonge, K Thielemans
• Journal: Blood (Blood) Vol. 87 Issue 10 Pg. 4390-8 (May 15 1996) ISSN: 0006-4971 [Print] United States
• PMID: 8639800 (Publication Type: Journal Article)

Chemical References

• Antibodies, Anti-Idiotypic
• Antibodies, Bispecific
• Antibodies, Monoclonal
• CD28 Antigens
• Muromonab-CD3

Topics

• Animals
• Antibodies, Anti-Idiotypic (administration & dosage, immunology, therapeutic use)
• Antibodies, Bispecific (administration & dosage, immunology, therapeutic use)
• Antibodies, Monoclonal (immunology, therapeutic use)
• CD28 Antigens (immunology)
• Cell Count
• Cricetinae
• Dose-Response Relationship, Immunologic
• Immunologic Memory
• Immunotherapy
• Injections, Intravenous
• Lymphocyte Activation
• Lymphoma, B-Cell (immunology, pathology, therapy)
• Male
• Mice
• Mice, Inbred BALB C
• Muromonab-CD3 (administration & dosage, immunology, therapeutic use)
• Neoplasm Transplantation
• T-Lymphocytes, Cytotoxic (immunology)