Efficacy of cytokine gene transfection may differ for autologous and allogeneic tumour cell vaccines.
Whole tumour cells are a logical basis for generating immunity against the cancers they comprise or represent. A number of human trials have been initiated using cytokine-transfected whole tumour cells of autologous (patient-derived) or allogeneic [major histocompatibility complex (MHC)-disparate] origin as vaccines. Although precedent exists for the efficacy of autologous-transfected cell vaccines in animal models, little preclinical evidence confirms that these findings will extrapolate to allogeneic-transfected cell vaccines. In order to address this issue a murine melanoma cell line (K1735) was transfected to secrete interleukin (IL)-2, IL-4, IL-7 or granulocyte-macrophage colony-stimulating factor (GM-CSF); cytokines currently in use in trials. The efficacy of these cells as irradiated vaccines was tested head-to-head in syngeneic (C3H) mice and in MHC-disparate (C57BL/6) mice, the former being subsequently challenged with K1735 cells and the latter with naturally cross-reactive B16-F10 melanoma cells. Whilst the GM-CSF-secreting vaccine was the most effective at generating protection in C3H mice, little enhancement in protection above the wild-type vaccine was seen with any of the transfections for the allogeneic vaccines, even though the wild-type vaccine was more effective than the autologous B16-F10 vaccine. Anti-tumour cytotoxic T-lymphocyte (CTL) activity was detected in both models but did not correlate well with protection, whilst in vitro anti-tumour interferon-gamma (IFN-gamma) secretion tended to be higher following the GM-CSF-secreting vaccine. Cytokine transfection of vaccines generally increased anti-tumour CTL activity and IFN-gamma secretion (T helper type 1 response). Further studies in other model systems are required to confirm this apparent lack of benefit of cytokine transduction over wild-type allogeneic vaccines, and to determine which in vitro assays will correlate best with protection in vivo.
The Onyvax Collaboration Laboratory, Division of Oncology, St. George's Hospital Medical School, London, UK.
S M
SM
Todryk
L J
LJ
Birchall
R
R
Erlich
N
N
Halanek
J K
JK
Orleans-Lindsay
A G
AG
Dalgleish
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D018929:Cell Culture Techniques; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012190:Retroviridae / Q000235:genetics; D013154:Spleen / Q000276:immunology; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured; D014611:Vaccination
D019496:Cancer Vaccines; D016207:Cytokines; D007371:Interferon-gamma