Immunotherapy with Antibody-Targeted HLA Class I Complexes: Results of in vivo Tumour Cell Killing and Therapeutic Vaccination

• Published in: Tumor biology 2007-01, Vol.28 (4), p.205-211
• Main Authors: Savage, Philip, Dyson, Julian, Milrain, Maggie, Mathews, Douglas, King, Ben, Chan, H.T. Claude, Barber, Linda, Epenetos, Agamemnon, Ogg, Graham, McMichael, Andrew, Glennie, Martin J., French, Ruth R.
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - metabolism; Cancer Vaccines; Cell Separation; Female; Histocompatibility Antigens Class I - chemistry; HLA Antigens - chemistry; Immunotherapy - methods; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms - metabolism; Research Article; T-Lymphocytes - metabolism; T-Lymphocytes, Cytotoxic - metabolism
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1159/000107416

Background: The delivery of antibody-targeted major histocompatibility complex (MHC) class I complexes containing immunogenic peptides to the surface of tumour cells allows cytotoxic T lymphocytes (CTLs) of non-tumour specificity to recognise and kill the tumour cell. Previous studies have demonstrated the activity of this system in vitro and in a simple pre-clinical model. This system has also been shown to be an effective method of expanding antigen-specific CTLs in vitro when used to target MHC class I complexes to the surface of B cells. Methods: Mice were immunised with ovalbumin and the survival of EL4Hu20 lymphoma cells targeted with H2-D b /Ova complexes and control MHC complexes was compared by FACS analysis. A tumour protection assay was performed where immunised mice were injected B16Hu20 melanoma cells targeted with H2-K b /Ova or control complexes. T cell expansion in vivo was examined by administering B cells targeted with MHC class I/peptide complexes and assessing T cell expansion by tetramer analysis. Results: In vivo killing of H2-D b /Ova-targeted lymphoma cells in the immunised mice was demonstrated with these cells present at only 12% of the level of the control cells. In contrast, in non-immunised mice the survival of H2-D b /Ova-targeted and control cells was comparable. In the tumour protection assay, injection of melanoma cells targeted with H2-K b /Ova complexes resulted in the development of only a solitary metastasis in each mouse. This compared to an average of 130 metastases in the control mice injected with B16Hu20 cells targeted with a control MHC peptide complex. In vivo CTL expansion was demonstrated after a single intravenous administration of Daudi B cells coated with H2-D b /Uty complexes produced an increase in the proportion of Uty-reactive CTLs from 3.3 to 21.5%. Conclusion: This study supports the development of antibody-delivered MHC complexes as a method of producing CTL-mediated lysis of cancer cells in vivo. As a therapeutic vaccine, the system may provide an effective approach for expanding oligoclonal T cell responses in vivo in the treatment of malignancy and infectious diseases.