Combinatorial Therapy for Liver Metastatic Colon Cancer: Dendritic Cell Vaccine and Low-Dose Agonistic Anti-4-1BB Antibody Co-Stimulatory Signal

Abstract

The combination of dendritic cell (DC) vaccine and 4-1BB ligation may be a suitable choice of immunotherapy for incurable cancer. However, at anti-tumor effector doses over 100 μg, 4-1BB Ab ligation is toxic to CD4(+) T cells, thus limiting its therapeutic use. A liver metastatic colon cancer model was established by hepatic injection of CT26 cells into Balb/c mice. Intraperitoneal administration of 1 × 10(6)/200 μL/mouse therapeutic-DCs (tumor lysate pulsed-DCs, P-DCs) began on d 7 after tumor cell inoculation. A P-DC injection was performed twice within a 1-wk interval. Agonistic anti 4-1BB Ab was intraperitoneally injected on d 7, 9, and 11 after tumor cell inoculation. Animals were sacrificed on d 21, and tumor growth was determined by weighing the liver with the tumor. In the 20 μg 4-1BB ligation group, significant induction of CD3(+)CD8(+) T cells was observed without toxicity to CD3(+)CD4(+) T cells. DC vaccine treatment induced tumor antigen-specific Th1 cytokine (IL-2 and IFN-γ) secretion from the splenic lymphocytes. Ligation of 4-1BB reduced the DC vaccine-related IL-10 secretion and regulatory T cell population. Compared with anti-tumor effect of DC vaccine or 20 μg 4-1BB Ab alone, the combination therapy significantly increased the tumor rejection power to the level observed with higher doses of 4-1BB Ab alone. The combination therapy did not induce high-dose 4-1BB-related toxicity with CD4(+) T cell reduction, but did significantly induce tumor antigen-specific IFN-γ secreting effector CD8(+) cytotoxic T cells. The data from our study reveal the value of using a DC vaccine combined with as little as 20 μg 4-1BB Ab as an improved immunotherapeutic for cancer.