Potentiation of the anti-tumor effects of imidazoquinoline immune response modifiers by cyclophosphamide.
The aim of the current study was to evaluate the influence of chemotherapeutic drugs on immunotherapy with Imidazoquinoline Toll-like Receptor (TLR) agonists in cancer. First, the previously described antitumor efficacy of TLR agonists [i.e. a TLR7 agonist (852A) and a dual TLR7/8 agonist (3M-011)] was confirmed in additional cancer models, and second the therapeutic potential of TLR agonists in combination with cyclophosphamide was investigated. The antitumor potential was evaluated against a panel of syngeneic tumor models; namely B16-F10 melanoma, M3 melanoma and MC-26 colon carcinoma. Systemic administration of either 3M-011 or 852A in these various syngeneic models induced significant antitumor activity as evidenced by delays in tumor growth curves. Combination of cyclophosphamide with either 3M-011 or 852A demonstrated that cyclophosphamide does not negatively interfere with the TLR agonist's antitumor effects, but may, depending on the dosing schedule, to actually potentiate the effect. These findings suggest that the immunomodulatory TLR agonists may be used in combination with cytotoxic agents in the treatment of cancer.
Merck Research Laboratories, Rahway, NJ, USA. calin_dumitru@merck.com
Calin D
CD
Dumitru
Mary A
MA
Antonysamy
Mark A
MA
Tomai
Kenneth E
KE
Lipson
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D007370:Interferon Type I / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D023421:Models, Animal; D016328:NF-kappa B / Q000276:immunology; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007370:Interferon Type I; C523097:N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide; D016328:NF-kappa B; D011804:Quinolines; D013449:Sulfonamides; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D003520:Cyclophosphamide