In situ tumor vaccination with adenovirus vectors encoding measles virus fusogenic membrane proteins and cytokines.
OBJECTIVE
To evaluate whether intratumoral expression of measles virus fusogenic membrane glycoproteins H and F (MV-FMG), encoded by an adenovirus vector Ad.MV-H/F, alone or in combination with local coexpression of cytokines (IL-2, IL-12, IL-18, IL-21 or GM-CSF), can serve as a platform for inducing tumor-specific immune responses in colon cancer.


METHODS
We used confocal laser scanning microscopy and flow cytometry to analyze cell-cell fusion after expression of MV-FMG by dye colocalization. In a syngeneic bilateral subcutaneous MC38 and Colon26 colon cancer model in C57BL/6 and BALB/c mice, we assessed the effect on both the directly vector-treated tumor as well as the contralateral, not directly vector-treated tumor. We assessed the induction of a tumor-specific cytotoxic T lymphocyte (CTL) response with a lactate dehydrogenase (LDH) release assay.


RESULTS
We demonstrated in vitro that transduction of MC38 and Colon26 cells with Ad.MV-H/F resulted in dye colocalization, indicative of cell-cell fusion. In addition, in the syngeneic bilateral tumor model we demonstrated a significant regression of the directly vector-inoculated tumor upon intratumoral expression of MV-FMG alone or in combination with the tested cytokines. We observed the highest anti-neoplastic efficacy with MV-FMG and IL-21 coexpression. The degree of tumor regression of the not directly vector-treated tumor correlated with the anti-neoplastic response of the directly vector-treated tumor. This regression was mediated by a tumor-specific CTL response.


CONCLUSIONS
Our data indicate that intratumoral expression of measles virus fusogenic membrane glycoproteins is a promising tool both for direct tumor treatment as well as for tumor vaccination approaches that can be further enhanced by cytokine coexpression.
Hoffmann
Dennis
D
Department of Molecular and Medical Virology, Institute of Microbiology and Hygiene, Ruhr-University Bochum, Bldg. MA, Rm. 6/40, D-44801 Bochum, Germany.
Bayer
Wibke
W
Wildner
Oliver
O
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002459:Cell Fusion; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors / Q000627:therapeutic use*; D019073:HT29 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008459:Measles virus / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000473:pathology; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D000098546:Interleukin-21
D019496:Cancer Vaccines; D016207:Cytokines; D007378:Interleukins; D014760:Viral Fusion Proteins; D000098546:Interleukin-21