Tumor mouse model confirms MAGE-A3 cancer immunotherapeutic as an efficient inducer of long-lasting anti-tumoral responses.
OBJECTIVE
MAGE-A3 is a potential target for immunotherapy due to its tumor-specific nature and expression in several tumor types. Clinical data on MAGE-A3 immunotherapy have raised many questions that can only be addressed by using animal models. In the present study, different aspects of the murine anti-tumor immune responses induced by a recombinant MAGE-A3 protein (recMAGE-A3) in combination with different immunostimulants (AS01, AS02, CpG7909 or AS15) were investigated.


RESULTS
Based on cytokine profile analyses and protection against challenge with MAGE-A3-expressing tumor, the combination recMAGE-A3+AS15 was selected for further experimental work, in particular to study the mechanisms of anti-tumor responses. By using MHC class I-, MHC class II-, perforin-, B-cell- and IFN-γ- knock-out mice and CD4+ T cell-, CD8+ T cell- and NK cell- depleted mice, we demonstrated that CD4+ T cells and NK cells are the main anti-tumor effectors, and that IFN-γ is a major effector molecule. This mouse tumor model also established the need to repeat recMAGE-A3+AS15 injections to sustain efficient anti-tumor responses. Furthermore, our results indicated that the efficacy of tumor rejection by the elicited anti-MAGE-A3 responses depends on the proportion of tumor cells expressing MAGE-A3.


CONCLUSIONS
The recMAGE-A3+AS15 cancer immunotherapy efficiently induced an antigen-specific, functional and long-lasting immune response able to recognize and eliminate MAGE-A3-expressing tumor cells up to several months after the last immunization in mice. The data highlighted the importance of the immunostimulant to induce a Th1-type immune response, as well as the key role played by IFN-γ, CD4+ T cells and NK cells in the anti-tumoral effect.
GlaxoSmithKline Vaccines, Rixensart, Belgium.
Catherine
C
Gérard
GlaxoSmithKline Vaccines, Rixensart, Belgium.
Nathalie
N
Baudson
GlaxoSmithKline Vaccines, Rixensart, Belgium.
Thierry
T
Ory
GlaxoSmithKline Vaccines, Rixensart, Belgium.
Jamila
J
Louahed
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D011994:Recombinant Proteins / Q000494:pharmacology
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D016207:Cytokines; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D011994:Recombinant Proteins