Routes of delivery for CpG and anti-CD137 for the treatment of orthotopic kidney tumors in mice.
We have found previously that the tumor cell lines, Renca (a renal cancer) and MC38 (a colon tumor) which had been injected subcutaneously in mice, could be successfully treated with a combination therapy of an oligodeoxynucleotide (CpG1826) (injected intratumorally) and anti-CD137 antibody (injected intraperitoneally). Thus the combination treatment was expected to initiate a "danger" signal via TLR9 on immune cells, and the anti-CD137 was expected to further activate T cells. In the present study, we found that several other tumor types injected subcutaneously could also be successfully treated with this combination therapy. In addition, we wished to determine if the treatment could work as effectively in an orthotopic metastatic model, which is more physiologically relevant to cancer in humans. Renca was selected as we were familiar with injecting this orthotopically into the outer cortex of the kidney in mice, and it spontaneously metastasizes to lung and abdominal sites. We tested various routes of delivery of CpG combined with intraperitoneal delivery of anti-CD137. Orthotopic tumors were injected with CpG intratumorally, using ultrasound-guided delivery on multiple occasions, combined with anti-CD137 intraperitoneally. A reduction in primary tumor size was observed following intratumoral injection of CpG compared to other treatments. We found that there was a statistically significant increase in survival of mice with orthotopic Renca tumor following intratumoral injection of CpG. However, we determined that the most effective route of delivery of CpG was intravenous, which led to further significantly enhanced survival of mice when combined with anti-CD137 intraperitoneally, likely due to inhibition of metastatic disease. Our data supports future development of this combination therapy for cancer.
Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Australia.
Jennifer A
JA
Westwood
Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Australia.
Titaina C U
TC
Potdevin Hunnam
Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Australia.
Hollie J
HJ
Pegram
Centre for Cancer Imaging, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Australia.
Rodney J
RJ
Hicks
Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia; Department of Immunology, Monash University, Prahran, Australia.
Phillip K
PK
Darcy
Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia; Department of Immunology, Monash University, Prahran, Australia.
Michael H
MH
Kershaw
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004333:Drug Administration Routes; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*
D000911:Antibodies, Monoclonal; D009838:Oligodeoxyribonucleotides; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9