Immunotherapy with antibody-targeted HLA class I complexes: results of in vivo tumour cell killing and therapeutic vaccination.
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%.


CONCLUSIONS
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.
Savage
Philip
P
Department of Medical Oncology, Charing Cross Hospital, London, UK. pmsavage@hhnt.nhs.uk
Dyson
Julian
J
Milrain
Maggie
M
Mathews
Douglas
D
King
Ben
B
Chan
H T Claude
HT
Barber
Linda
L
Epenetos
Agamemnon
A
Ogg
Graham
G
McMichael
Andrew
A
Glennie
Martin J
MJ
French
Ruth R
RR
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines; D002469:Cell Separation; D005260:Female; D006680:HLA Antigens / Q000737:chemistry*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
D019496:Cancer Vaccines; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I