For more than a decade, the cancer drug imatinib (Gleevec®) has been a striking success among targeted therapies, which prevent disease by impeding specific molecular mechanisms. In addition to treating blood cancers, imatinib has also proved effective against gastrointestinal stromal tumor (GIST), a rare cancer of the digestive tract, by blocking a mutated protein called KIT.
Now Memorial Sloan-Kettering researchers have made a surprising discovery about imatinib’s mode of action against GIST: The drug appears to work partly by stimulating the immune system to attack the cancer. The finding, made by a team led by surgeon and immunologist Ronald P. DeMatteo, was reported in the September issue of Nature Medicine. [PubMed Abstract]
The researchers first gave imatinib to mice that develop GIST spontaneously and saw the tumors shrink. But close inspection also revealed something unexpected about immune cells present in the tumors and nearby lymph nodes. A group of immune cells called cytotoxic T cells — which recognize and kill foreign invaders — had been activated and multiplied. In addition, another group of immune cells called regulatory T cells — which suppress the immune response — had diminished in number due to programmed cell death.
Imatinib appears to block a protein called Ido, which researchers think tumors use to promote regulatory T cell function and thus prevent immune attack. Neutralizing Ido’s effect alters the ratio among the T cells, giving the cytotoxic T cells the upper hand to unleash the immune response. These findings were verified in human GIST cell lines and in fresh specimens taken from GIST patients.
The scientists then demonstrated that combining imatinib with therapies that more directly modulate the immune system could be a powerful approach to treating GIST and other cancers. They gave the mice imatinib along with an antibody that blocks CTLA-4, a protein that acts as a brake on the immune response. The combination therapy was more effective than imatinib alone at shrinking the tumors.
“Our study establishes proof of principle that imatinib and an immune agent are synergistic and provides the rationale to conduct a novel clinical trial in patients with advanced GIST,”
Dr. DeMatteo says. “Ultimately, we hope this approach will also be effective in other tumor types treated with molecular agents.”