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Allogeneic Tumor Cells Expressing Fusogenic Membrane Glycoproteins as a Platform for Clinical Cancer Immunotherapy

Authors' Affiliations: ¹ Cancer Research UK Clinical Center, St. James's University Hospital, Leeds, United Kingdom; ² Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota; ³ Somers Cancer Research Building, Southampton General Hospital, Southampton; and ⁴ Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom

Requests for reprints: Richard Vile, Molecular Medicine Program, Mayo Clinic, Guggenheim 1836, 200 1st Street Southwest, Rochester, MN 55902. Phone: 507-284-9941; Fax: 507-266-2122; E-mail: vile.richard{at}mayo.edu.

Purpose: 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.

Experimental Design: 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.

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