The development of cancer immunotherapy is one of the major advances in medicine. Unlike chemotherapy, which kills the cancer cells directly, immunotherapy enlists the help of the immune system, which then kills the cancer cells. Some forms of immunotherapy use substances called “checkpoint inhibitors”—they block mechanisms that cancer cells use to shut down the immune system. In other forms of immunotherapy, immune cells are removed from the patient, modified in a way that allows them to help fight cancers, multiplied in the laboratory, and injected back into the patient.However, cancer immunotherapy works only for some types of cancer and, even then, only a fraction of patients responds. Now, results from a new study carried out in mice (Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses) shows that the outcome can be improved by using a combination of four different therapies. The combination activates both innate and adaptive immunity, resulting in a coordinated attack that leads to the complete disappearance of large, aggressive tumors.
The combination therapy consists of four components: an antibody targeted to the tumor; a vaccine targeted to the tumor; the cytokine IL-2; and a molecule that blocks PD1, a receptor found on T cells. Each of these molecules plays a critical role in enhancing the overall immune response to the tumor. Antibodies stimulate the recruitment of additional immune cells that help to activate T cells; the vaccine stimulates proliferation of T cells that can attack the tumor; IL-2 helps the T cell population to expand quickly; and the anti-PD1 molecule helps T cells stay active longer.
The researchers tested the combination treatment in different strains of mice that were implanted with melanoma, lymphoma, and breast cancer—three different types of tumors able to suppress the immune response directed against them. They found that in all strains of mice, about 75 percent of the tumors were completely eliminated. After six months, the researchers injected tumor cells into the same mice. They found that the mice’ immune systems were able to completely clear the tumor cells. Thus, the combination therapy allowed the immune system to “remember” the target and destroy new cancer cells that appeared after the treatment ended.
The immune system components responsible for the regression of large, established tumors were CD8+ T cells, cross-presenting dendritic cells, and several other innate immune cell subsets. The combination therapy induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake, and promoted antigen spreading.
Darrell Irvine, senior author of the study, said in a press release: “We have shown that with the right combination of signals, the endogenous immune system can routinely overcome large immunosuppressive tumors, which was an unanswered question.”