Of all the horrors that people fighting cancer have to handle, treatments might be among the toughest. Surgery, radiation, and chemotherapy all have awful side effects because they kill healthy cells along with the tumor. Researchers have spent decades trying to target therapeutic agents only to the cancer cells. A new report in Nature Medicine describes a therapeutic agent that's not even that cytotoxic—it's only rendered harmful when it gets to the targeted cancer cells.

Monoclonal antibodies are produced by cells that can grow indefinitely, providing us with an essentially infinite supply of antibodies that recognize a single, specific molecule. They are one of the most successful targeted cancer therapies that have been tried. But that success has been limited by toxicity issues.

Now, monoclonal antibodies have been paired with photodynamic therapy, which harnesses a photosensitizing chemical agent to allow light of a chosen wavelength to kill cells. This approach has not been used much against cancer because the photosensitizing agents couldn't be targeted specifically to tumor cells.

A group at the National Cancer Institute has linked the two technologies by attaching a photosensitizing agent to trastuzumab, a monoclonal antibody that binds to the human epidermal growth factor receptor 2 (HER2), a protein expressed by many cancer cells. (Trastuzumab’s trade name is Herceptin.)

A key to making this work was using a hydrophilic (water soluble) photosensitizer. Most photosensitizing agents are hydrophobic, and therefore difficult to connect to an antibody without blocking the antibody’s ability to bind to its target. Moreover, most photosensitizers need to be internalized by the cell to be effective, and it is difficult for light to reach them there.

By linking a hydrophilic photosensitizer to trastuzumab, Mitsunaga et al. ensured it was effective when bound to the outside of the tumor cell membrane. They found that tumor cells expressing HER2—both those in a culture dish and those implanted into mice—treated with their compound were killed upon exposure to near infrared light. The compound produced no toxicity in cells in the absence of light, and the light was harmless on its own. As a side bonus, the photosensitizer is fluorescent. This fluorescence can be used diagnostically to determine exactly where the cancer cells are, and thus where to shine the killing light. Its disappearance can also measure the efficacy of treatment.

They are not sure exactly how this works. Conventional phototherapy relies on the generation of reactive oxygen species (ROS) to kill cells, which is why it is important to target them to tumor cells. But adding a molecule that neutralizes these ROS only partially blocked cell death, so another mechanism must be contributing to the killing. Because their agent must be bound to the cell membrane to work, and because it kills cells relatively quickly, the scientists hypothesize that the cell death was caused by the rapid local heating of water.

They conclude that their photosensitizer can be linked to different monoclonal antibodies to target different types of tumors. And they call their new therapy PIT, for photo-immuno-therapy. If it ends up working in the clinic, it could make conventional cancer therapies really seem like the pits.

doi:10.1038/nm.2554