Activation of the human immune system by chemotherapeutic or targeted agents combined with the oncolytic parvovirus H-1.
BACKGROUND
Parvovirus H-1 (H-1PV) infects and lyses human tumor cells including melanoma, hepatoma, gastric, colorectal, cervix and pancreatic cancers. We assessed whether the beneficial effects of chemotherapeutic agents or targeted agents could be combined with the oncolytic and immunostimmulatory properties of H-1PV.


METHODS
Using human ex vivo models we evaluated the biological and immunological effects of H-1PV-induced tumor cell lysis alone or in combination with chemotherapeutic or targeted agents in human melanoma cells +/- characterized human cytotoxic T-cells (CTL) and HLA-A2-restricted dendritic cells (DC).


RESULTS
H-1PV-infected MZ7-Mel cells showed a clear reduction in cell viability of >50%, which appeared to occur primarily through apoptosis. This correlated with viral NS1 expression levels and was enhanced by combination with chemotherapeutic agents or sunitinib. Tumor cell preparations were phagocytosed by DC whose maturation was measured according to the treatment administered. Immature DC incubated with H-1PV-induced MZ7-Mel lysates significantly increased DC maturation compared with non-infected or necrotic MZ7-Mel cells. Tumor necrosis factor-α and interleukin-6 release was clearly increased by DC incubated with H-1PV-induced SK29-Mel tumor cell lysates (TCL) and was also high with DC-CTL co-cultures incubated with H-1PV-induced TCL. Similarly, DC co-cultures with TCL incubated with H-1PV combined with cytotoxic agents or sunitinib enhanced DC maturation to a greater extent than cytotoxic agents or sunitinib alone. Again, these combinations increased pro-inflammatory responses in DC-CTL co-cultures compared with chemotherapy or sunitinib alone.


CONCLUSIONS
In our human models, chemotherapeutic or targeted agents did not only interfere with the pronounced immunomodulatory properties of H-1PV, but also reinforced drug-induced tumor cell killing. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a pronounced DC maturation, better cytokine release and cytotoxic T-cell activation compared with agents alone. Thus, the clinical assessment of H-1PV oncolytic tumor therapy not only alone but also in combination strategies is warranted.
First Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany. moehler@mail.uni-mainz.de
Markus
M
Moehler
Maike
M
Sieben
Susanne
S
Roth
Franziska
F
Springsguth
Barbara
B
Leuchs
Maja
M
Zeidler
Christiane
C
Dinsart
Jean
J
Rommelaere
Peter R
PR
Galle
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D052661:H-1 parvovirus / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D008954:Models, Biological; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology; D010322:Parvoviridae Infections / Q000378:metabolism / Q000821:virology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000821:virology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014764:Viral Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; D014764:Viral Proteins