title: Intratumoral delivery of low doses of anti-CD40 mAb combined with monophosphoryl lipid a induces local and systemic antitumor effects in immunocompetent and T cell-deficient mice.
abstract: In this study, an agonistic anti-CD40 monoclonal antibody was combined with monophosphoryl lipid A (MPL), a nontoxic derivative of lipopolysaccharide and agonist of toll-like receptor-4, to assess the immunomodulatory and antitumor synergy between the 2 agents in mice. Anti-CD40 was capable of priming macrophages to subsequent ex vivo activation by MPL in immunocompetent and T-cell-depleted mice. Intraperitoneal injections of anti-CD40+MPL induced additive to synergistic suppression of poorly immunogenic B16-F10 melanoma growing subcutaneously in syngeneic mice. When anti-CD40+MPL were injected directly into the subcutaneous tumor, the combination treatment was more effective, even with a 25-fold reduction in dose. Low-dose intratumoral treatment also slowed the growth of a secondary tumor growing simultaneously at a distant, untreated site. Antitumor effects were also induced in severe combined immunodeficiency mice and in T-cell-depleted C57BL/6 mice. Taken together, our results show that the antitumor effects of anti-CD40 are enhanced by subsequent treatment with MPL, even in T-cell-deficient hosts. These preclinical data suggest that an anti-CD40+MPL combined regimen is appropriate for clinical testing in human patients, including cancer patients who may be immunosuppressed from prior chemotherapy.
authors.affiliation: Department of Human Oncology, University of Wisconsin-Madison, Madison 53705. WI, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Van De Voort
authors.forename: Mildred A R
authors.initials: MA
authors.lastname: Felder
authors.forename: Richard K
authors.initials: RK
authors.lastname: Yang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D019013:CD40 Antigens / Q000276:immunology*; D005260:Female; D007074:Immunoglobulin G / Q000008:administration & dosage; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008264:Macrophages / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010529:Peritoneal Cavity / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D007074:Immunoglobulin G; D008050:Lipid A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C048436:monophosphoryl lipid A