New cancer therapy helps tumors "go to the light"
Scientists at the National Cancer Institute (NCI), of the National Institutes of Health (NIH), have announced the development of a new light-based cancer therapy. The treatment, known as photoimmunotherapy (PIT), uses light to selectively kill cancer cells, and could have the potential to work against breast, lung and prostate tumors, as well as cancer cells found in the blood such as leukemias. The results from the study were published online in Nature on Nov. 6.
The PIT developed by the NIH researchers combines a monoclonal antibody (MAb), which recognizes specific proteins on the surface of cancer cells, with a photosensitizer, a molecule that rapidly damages cells when exposed to light of the proper wavelength (near-infrared). As current photodynamic therapies have a tendency to damage surrounding healthy cells, the researchers hoped the combination would allow for greater targeting with the PIT.
"The uniqueness of PIT is PIT can kill cancer cells even next to normal cells, without damaging normal cells," says Dr. Hisataka Kobayashi, chief scientist in the Molecular Imaging Program at NCI's Center for Cancer Research. "Cancer cells mechanically crashed by damaging the cell membrane within seconds to minutes by shining [near-infrared] light." He adds that while conventional therapies such as radiation and chemo damage normal cells, PIT theoretically stands to have significantly fewer side effects.
Researchers settled on IR700, a near-infrared fluorescent dye, as having the most favorable chemical properties. They linked IR700 with three different MAbs, including antibodies that target HER2 (overexpressed in some breast cancers), EGFR (overexpressed in some lung, pancreatic and colon cancers) and PSMA (overexpressed by prostate cancers). When the cancer cells bound MAb-IR700 and were subsequently exposed to near-infrared light, the targeted cells died rapidly while cells without the ability to bind the compound were unharmed. In mouse models of cancer, when treated with MAb-IR700, even one dose of near-infrared light led to significant tumor shrinkage.
PIT utilizing MAb-IR700 also differs from conventional photosensitizers in terms of effectiveness. While the light required to activate conventional photosensitizers can only penetrate through about 0.8 centimeters of tissue (approximately a third of an inch), the near-infrared light used in conjunction with IR700 can penetrate to a depth of several centimeters.
"The ability to join different MAbs to IR700 means that this technique might be used as a non-invasive guide to monitor the results of treatments," said Kobayashi in a press release. "Although more testing will be needed, we believe this PIT method has the potential to replace some surgical, radiation and chemotherapy treatments."
The required antibody doses for diagnosis were found to be significantly lower than the doses required for therapy, and the scientists noted that since targeted tumors shrunk and disappeared after MAb-IR700 exposure, the therapy represents a potential means of controlling cancer with lower doses of MAb than are usually administered. The compound can also be used for monitoring therapy, as it emits a small amount of light.
In their experiments with mice, the researchers found that a 10-fold dose of the conjugate in a week, or 100-fold dose of IR700 by itself "did not cause any acute and sub-acute side effects," Kobayashi notes, adding that "all free or catabolized IR or IR700-amino acids were excreted into urine very quickly, over 97 percent within a day." He adds that they have no concerns in terms of toxicity related to PIT, as "no toxicity was shown with this dose of constant wave or 10-fold bright pulse light." The largest side effect noted, he says, was that mouse body temperature did increase when the mice were exposed to maximum light to their entire bodies. Several mice did die due to crash syndrome when large tumors were treated, which Kobayashi says was due to too many cancer cells crashing within a minute, releasing potassium and leading to heart arrest. The therapy should be slowed down to eliminate this problem, he says.
There are several steps ahead of them to advance this therapy, Kobayashi explains, starting with trying to determine "the best regimen of combining PIT for dosing MAb-IR700 and timing/dose of shining [near-infrared] light."
"We now know immediate cell crash by PIT can promote the MAb-IR700 reach to the deep-sitting hidden cancer cell, and second dose of light can clear these remnant cells," says Kobayashi.
The researchers will also work to establish a monitoring method to evaluate the immediate effects of PIT. PIT can crash 99 percent of cancer cells within 10 to 15 minutes, he notes, but tumor size stays the same before the cell debris is cleaned up by microphages. As such, they will work to find a diagnosis method to ensure all cancer cells crash.
"We believe this PIT method is already mature enough to apply to the clinical trial," says Kobayashi. "We [will] try to make a GMP compound for proceeding PIT to the clinical trial."