A new form of photodynamic therapy dubbed photoimmunotherapy, or PIT, destroys cancer cells in mice without harming surrounding normal tissue. This light-based cancer therapy technique could theoretically work against tumors in humans, such as those of the breast, lung and prostate, as well as cancer cells in the blood, such as leukemias. Current photodynamic therapy is not specific for cancer cells, resulting in damage to surrounding healthy tissue. Therefore, researchers at the National Cancer Institute (NCI) set out to develop a light therapy that could more accurately target cancer cells while sparing a greater number of normal cells. PIT couples a monoclonal antibody (MAb), which recognizes specific proteins on the surface of cancer cells, with a photosensitizer, a molecule that rapidly damages cells when it is exposed to near-IR light. The NCI researchers’ hope was that the photosensitizer-MAb combination would, by delivering the photosensitizer to cancer cells targeted by the MAb, selectively kill those cells after exposure to near-IR light. Co-cultured cells with or without target (HER2) expression are cultured in the medium containing antibody-conjugate and shone with near-IR light for 2 min (PIT). Only HER2+ cells (arrow) become swollen and irregular shapes and die. However, HER2- cells do not change at all and survive without damage. (Image: Hisataka Kobayashi, NCI) After evaluating a large number of photosensitizers, the scientists found that a near-IR fluorescent dye called IR700 had the most favorable chemical properties. The scientists chemically linked IR700 to three different MAbs, including antibodies that target HER2, which is overexpressed by some breast cancers; EGFR, which is overexpressed by some lung, pancreatic and colon cancers; and PSMA, which is overexpressed by prostate cancers. The researchers found that when cancer cells bound MAb-IR700 and were exposed to near-IR light, the targeted cells rapidly died, whereas cells lacking the ability to bind the complex were unharmed. When the complex was tried in mouse models of cancer, even a single dose of light resulted in dramatic tumor shrinkage in mice that had been given MAb-IR700. Photoimmunotherapy using MAb-IR700, unlike conventional photosensitizers (which can cause damage to healthy tissue), does not appear to harm normal cells. Whereas the light that is required to activate conventional photosensitizers can penetrate through only about 0.8 cm of tissue, the near-IR light used to activate IR700 can penetrate tissue to a depth of several centimeters. The study also found that antibody doses required for diagnosis were significantly lower than those required for therapy. Nevertheless, after MAb-IR700 exposure, the targeted tumors decreased in size and eventually disappeared, suggesting a potential means of controlling cancers with far lower doses of MAb than are usually administered to cancer patients, according to the NCI scientists. Because the MAb-IR700 compound also emits a small amount of light, it can be used to monitor therapy as well. “The ability to join different MAbs to IR700 means that this technique might be used as a noninvasive guide to monitor the results of treatments,” said Hisataka Kobayashi, chief scientist in the Molecular Imaging Program at NCI’s Center for Cancer Research. “Although more testing will be needed, we believe this PIT method has the potential to replace some surgical, radiation and chemotherapy treatments.” The group’s findings were published online Nov. 6 by Nature Medicine. For more information, visit: www.cancer.gov
Photosensitizers