Regression of established AB1 murine mesothelioma induced by peritumoral injections of CpG oligodeoxynucleotide either alone or in combination with poly(I:C) and CD40 ligand plasmid DNA.
BACKGROUND
Stimulation of the CD40 receptor using an agonistic anti-CD40 antibody can slow the growth of AB1 tumors. Stimulation of the GITR receptor may also have antitumor activity by countering the immunosuppressive effects of regulatory CD4 T cells. Similarly, agonists for Toll-Like Receptors (TLR) such as CpG oligodeoxynucleotides (TLR9 agonist) have activity against AB1 tumors. Combinations of CpG with CD40 ligand and polyinosinic-polycytidylic acid (poly(I:C), TLR3 agonist) may be even stronger than CpG alone. The synergistic effects of these combinations have been tested in other tumor types but not in mesothelioma.


METHODS
Established AB1 mesothelioma tumors were injected with either plasmid DNA encoding a novel 4-trimer form of murine CD40 ligand (pSP-D-CD40L), GITR ligand (GITRL), or control plasmid DNA. In addition, CpG with or without poly(I:C) was also injected intratumorally.


RESULTS
Plasmid injections of pSP-D-CD40L or pSP-D-GITRL, had no significant antitumor effect, possibly reflecting the difficulty of administering DNA injections into this very dense tissue. However, the injection of CpG with or without poly(I:C) strongly suppressed tumor growth and led to long-term tumor-free survival. The response to a triple combination of pSP-D-CD40L + CpG + poly(I:C) was demonstrated by an increase in intratumoral CD8 T cells and a dramatic increase in F4/80 macrophages.


CONCLUSIONS
Intratumoral injections of plasmid DNAs encoding highly active forms of either CD40 ligand or GITR ligand had no significant antitumor effects in this model, although improved DNA delivery techniques could possibly improve this strategy. In contrast, intratumoral CpG injections had significant antitumor effects and there were indications that CpG plus poly(I:C) was even more effective. Taken together, these data confirm previous reports that immune stimulants, especially CpG TLR9 agonists, have potential as a treatment for mesothelioma.
Stone
Geoffrey W
GW
Department of Medicine, University of California San Diego, La Jolla, California 92093-0679, USA.
Barzee
Suzanne
S
Snarsky
Victoria
V
Santucci
Camila
C
Tran
Brian
B
Kornbluth
Richard S
RS
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D023201:CD40 Ligand / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D004247:DNA / Q000276:immunology; D004357:Drug Synergism; D015552:Injections, Intralesional; D007369:Interferon Inducers / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D008654:Mesothelioma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D010957:Plasmids; D011070:Poly I-C / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D015996:Survival Rate; D048069:Tumor Necrosis Factors / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D007369:Interferon Inducers; D009838:Oligodeoxyribonucleotides; C478967:TNFSF18 protein, human; D048069:Tumor Necrosis Factors; D023201:CD40 Ligand; D004247:DNA; D011070:Poly I-C