New Cancer Vaccine Strategy

A two-headed small molecule could marshal a cancer patient’s immune system to seek out and destroy prostate tumor cells.

In current immunotherapy strategies, researchers target cancer cells by linking chemotherapy drugs or radionuclides to antibodies for proteins on the cells’ surface. Although the antibodies shuttle most of these toxic agents to cancer cells, the drugs can still hit healthy cells, leading to unwanted side effects.

“We wanted to develop a strategy in which a patient’s own immune system, rather than a toxic compound, kills prostate cancer cells,” says David A. Spiegel, a chemist at Yale University.

To do so, Spiegel and his collaborators designed a molecule that consists of two chemical groups linked together: 2-[3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA) and 2,4-dinitrophenyl (DNP). Other researchers have shown that DUPA selectively binds to a unique prostate cancer cell protein (Mol. Pharm., DOI: 10.1021/mp900069d). DNP is a well-known environmental contaminant that, for unknown reasons, most people already have antibodies against. The team envisioned that the DUPA end of the molecule would grab on to prostate cancer cells and the DNP end would attract these circulating antibodies to trigger an immune response to destroy the cells.

The researchers tested their hypothesis in mice that had human prostate tumors grafted under the skin of their right flanks. After two weeks of three treatments per week of the two-headed molecule, tumors in the mice were about 80% smaller than those in mice treated with DUPA alone (ACS Chem. Biol., DOI: 10.1021/cb200222s). When the researchers analyzed tumor tissue samples from mice treated with the two-headed molecule, they discovered that lymphocytes called natural killer cells had infiltrated the tumor.

Laura L. Kiessling, a biochemist at the University of Wisconsin, Madison, says that, because the small molecule is modular, the new approach “lays the groundwork” for targeting not only prostate cancer, but also other cancer types. “In principle, any cell-targeting agent can be combined with an antibody recruitment agent,” she says.