Long-lasting Complete Regression of Established Mouse Tumors by Counteracting Th2 Inflammation

Mice with intraperitoneal ID8 ovarian carcinoma or subcutaneous SW1 melanoma were injected with monoclonal antibodies (mAbs) to CD137(+) PD-1(+) CTLA4 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-gamma and TNF-alpha 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 CD4(+) Foxp3(+) regulatory T (Treg) cells and to CD11b(+) Gr-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 CD137(+) PD-1(+) CTLA4(+) CD19 can induce complete regression and dramatically prolong survival also in the TC1 carcinoma and B16 melanoma models, suggesting that the approach has general validity.