title: Long-lasting complete regression of established mouse tumors by counteracting Th2 inflammation.
abstract: Mice with intraperitoneal ID8 ovarian carcinoma or subcutaneous SW1 melanoma were injected with monoclonal antibodies (mAbs) to CD137PD-1CTLA4 7-15 days after tumor initiation. Survival of mice with ID8 tumors tripled and >40% of mice with SW1 tumors remained healthy >150 days after last treatment and are probably cured. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity, required CD4 cells and involved CD8 cells and NK cells to a less extent. The 3 mAb combination significantly decreased CD19 cells at tumor sites, increased IFN-γ and TNF-α producing CD4 and CD8 T cells and mature CD86 dendritic cells (DC), and it increased the ratios of effector CD4 and CD8 T cells to CD4Foxp3 regulatory T (Treg) cells and to CD11bGr-1 myeloid suppressor cells (MDSC). This is consistent with shifting the tumor microenvironment from an immunosuppressive Th2 to an immunostimulatory Th1 type and is further supported by PCR data. Adding an anti-CD19 mAb to the 3 mAb combination in the SW1 model further increased therapeutic efficacy. Data from ongoing experiments show that intratumoral injection of a combination of mAbs to CD137PD-1CTLA4CD19 can induce complete regression and dramatically prolong survival also in the TC1 carcinoma and B16 melanoma models, suggesting that the approach has general validity.
authors.affiliation: Department of Pathology, Harborview Medical Center, University of Washington, Seattle, WA 98104-2499, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Dai
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.forename: Yuen Yee
authors.initials: YY
authors.lastname: Yip
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Feng
authors.forename: Kecheng
authors.initials: K
authors.lastname: He
authors.forename: Viorica
authors.initials: V
authors.lastname: Popov
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Hellstrom
authors.forename: Karl Erik
authors.initials: KE
authors.lastname: Hellstrom
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D016130:Immunophenotyping; D007249:Inflammation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000276:immunology / Q000401:mortality / Q000628:therapy; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D000939:Epitopes; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9