Arming parvoviruses with CpG motifs to improve their oncosuppressive capacity.
Oncolytic viruses represent novel tools for cancer treatment. Besides specifically killing cancer cells (oncolysis), these agents also provide danger signals, prompting the immune system to eliminate virus-infected tumours. As a consequence of oncolytic events, the innate and adaptive immune systems gain access to tumour antigens, which result in cross-priming and vaccination effects. Here the aim was to see whether we could enhance this adjuvant capacity by incorporating immunostimulatory CpG motifs into the single-stranded genome of an oncolytic parvovirus (H-1PV). We engineered 2 CpG-enriched H-1PV variants (JabCG1 and JabCG2), preserving both the replication competence and the oncolytic features of the parental virus. In keeping with their increased CpG content, the JabCG1 and JabCG2 genomes proved in vitro to be more potent triggers of TLR-9-mediated signalling than wild-type H-1PV DNA. Antitumour activity was evaluated in a rat model of MH3924A hepatoma lung metastases, where an infection with parental or modified viruses served as an ex vivo adjuvant to a subcutaneously administered autologous cell vaccine. In this setup, which excludes direct oncolytic effects on metastases, the JabCG2 vector displayed enhanced immunogenicity, inducing markers of cellular immunity (IFN gamma) and dendritic cell activation (CD80, CD86) in mediastinal (tumour-draining) lymph nodes. This led to a significantly reduced metastatic rate (50%) as compared to other vaccination schedules (H-1PV-, JabCG1-, JabGC- or mock-treated cells). The data provide proof of principle that increasing the number of immunostimulatory CpG motifs within oncolytic viruses makes it possible to improve their overall anticancer effect by inducing antitumour vaccination.
Raykov
Zahari
Z
Infection and Cancer Program, Abteilung F010 and Inserm U701, Deutsches Krebsforschungszentrum, Heidelberg, Germany. z.raykov@dkfz.de
Grekova
Svetlana
S
Leuchs
Barbara
B
Aprahamian
Marc
M
Rommelaere
Jean
J
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018899:CpG Islands; D017931:DNA Primers; D004279:DNA, Viral; D050130:Oncolytic Virotherapy; D017992:Parvovirus / Q000235:genetics / Q000502:physiology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D004279:DNA, Viral