Allogeneic tumor cells expressing fusogenic membrane glycoproteins as a platform for clinical cancer immunotherapy.
OBJECTIVE
Fusogenic membrane glycoproteins (FMG), such as the vesicular stomatitis virus G glycoprotein (VSV-G), represent a new class of gene therapy for cancer that cause cytotoxic fusion on expression in tumor cells. In addition, FMG-mediated tumor cell death stimulates antitumor immunity, suggesting potential applications for FMG-expressing cellular vaccines. This study addresses the promise of FMG-expressing allogeneic tumor cells, which are most practical for clinical use, as a novel platform for ex vivo and in situ vaccination.


METHODS
Murine B16 melanoma-derived cell lines expressing autologous or allogeneic MHC class I, expressing fusogenic or nonfusogenic VSV-G, were used to vaccinate mice in vivo against a live tumor challenge. Exosome-like vesicles released by fusing allogeneic cells (syncitiosomes) and intratumoral injection of fusing vaccines were also tested as novel therapeutic strategies for their antitumor effects.


RESULTS
Expression of fusogenic VSV-G enhanced the immunogenicity of an allogeneic cellular vaccine, which was more effective than a fusing autologous vaccine. Allogeneic syncitiosomes were only as effective as cellular vaccines when administered with adjuvant, demonstrating that syncitiosomes cannot account entirely for the mechanism of immune priming. Intratumoral injection of FMG-expressing allogeneic cells led to significant tumor regression using both fusogenic or nonfusogenic VSV-G. However, specific priming against tumor-associated antigenic epitopes and protection against secondary rechallenge only occurred if the initial vaccine was competent for cell fusion.


CONCLUSIONS
FMG-expressing allogeneic tumor cells are a potent source of antitumor vaccines. Syncitiosomes given with adjuvant and intratumoral injection of fusing cells represent novel strategies well-suited to clinical translation.
Cancer Research UK Clinical Center, St. James's University Hospital, Leeds, UK.
Fiona
F
Errington
Andrew
A
Bateman
Tim
T
Kottke
Jill
J
Thompson
Kevin
K
Harrington
Alison
A
Merrick
Paul
P
Hatfield
Peter
P
Selby
Richard
R
Vile
Alan
A
Melcher
D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D022162:Cytoplasmic Vesicles / Q000276:immunology; D015870:Gene Expression; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012074:Remission Induction; D013997:Time Factors; D014162:Transfection; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000276:immunology
D019496:Cancer Vaccines; C028391:G protein, vesicular stomatitis virus; D006183:H-2 Antigens; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins