Recombinant vesicular stomatitis virus targeted to Her2/neu combined with anti-CTLA4 antibody eliminates implanted mammary tumors.
Vesicular stomatitis virus (VSV) is being developed for cancer therapy. We created a recombinant replicating VSV (rrVSV) that preferentially infected Her2/neu expressing breast cancer cells. We now used this rrVSV to treat macroscopic peritoneal tumor implants of a mouse mammary tumor cell line stably transfected to express Her2/neu. rrVSV therapy alone prolonged survival but did not cure any animals. rrVSV therapy combined with antibody to TGFb or antibody to IL-10 receptor (IL-10R) each produced cure in one of six animals. Strikingly, rrVSV therapy combined with anti-CTLA4 monoclonal antibody (MAb) produced cure in four of five animals. Anti-CTLA4 MAb was only effective when administered within one day of rrVSV therapy. Cure required CD4 T-cells early (<7 days) and late (>7 days) after rrVSV therapy whereas CD8 T-cells were required only late (>7 days) after rrVSV therapy. Surviving animals were resistant to re-challenge with D2F2/E2 suggesting a memory immune response. Histopathologic analysis demonstrated a dense inflammatory infiltrate of tumor nodules within days of therapy and foamy histiocytes replacing the tumor nodules 2 weeks following therapy. These studies demonstrate that targeted rrVSV combined with anti-CTLA4 MAb can eliminate established macroscopic tumor implants by eliciting an anti-tumor CD4 and CD8 T-cell immunologic response.
Gao
Y
Y
Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Whitaker-Dowling
P
P
Griffin
J A
JA
Barmada
M A
MA
Bergman
I
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060908:CTLA-4 Antigen; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology*; D013997:Time Factors; D014162:Transfection; D018116:Vesiculovirus
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse