Science Magazine - Tiny nanoparticles, far smaller than the width of a human hair, might help the body’s own immune system fight tumors, a new study shows. In experiments with mice, the nanoparticle-based therapy not only wiped out the original targeted breast cancer tumors, but metastases in other parts of the body as well. Human clinical trials with the new therapy could begin within the next several months, researchers say.
The search for drugs that spur the immune system to fight tumors is one of the hottest fields in cancer research. Immune sentries, known as T cells, are normally on the prowl for suspicious looking targets, such as bacterial invaders and potential tumor cells. If they recognize one, they sound the alarm, inducing other immune cells to mount a larger response. However, the T cells’ alarm can be muted by so-called immune checkpoints, other proteins on the surface of normal cells that tamp down the immune response to prevent harmful autoimmune reaction to normal tissue. Tumor cells often over express these checkpoint molecules, putting the brakes on the immune system’s search and destroy work.
To overcome that problem, pharmaceutical companies have developed a number of different antibody proteins that block these overexpressed checkpoint molecules and enable the immune system to target tumors. In cases where there are lots of T cells in the vicinity of a tumor, or where tumor cells have undergone large numbers of mutations, which creates additional targets for immune sentries, T cells will signal a full-fledged immune response to the cancer. Such cancer immunotherapy can add extra years to patients’ lives.
However, existing cancer immunotherapy drugs work in only 20% to 30% of patients. In some cases, even when the checkpoint molecules are blocked that there are too few active T cells around to sound the immune alarm, says Jedd Wolchok, a cancer immunotherapy expert at the Memorial Sloan Kettering Cancer Center in New York City. In others, he says, tumors don’t display enough of the T cell’s targets, so-called tumor antigens, on their surface.
But a seemingly unrelated puzzle offered the prospect of boosting immunotherapy’s effectiveness. Oncologists have long known that in rare cases, after patients receive radiation therapy to shrink a tumor, the immune system will mount an aggressive response that wipes out not only the tumor, but metastases throughout the body that hadn’t been treated with the radiation. Researchers now think that irradiation sometimes kills tumor cells in a manner that exposes new antigens to T cells, priming them to target other tumor cells that carry them as well, says Wenbin Lin, a chemist at the University of Chicago in Illinois, and one of the authors of the current study.
Lin wanted to see whether he could use nontoxic nanoparticles to sensitize the immune system in a similar way. Getting the nanoparticles themselves past the immune system isn’t easy. If they’re too big, cells in the blood called macrophages gobble them up. And blood proteins tend to coat the particles, facilitating their uptake. In recent years Lin’s team devised a method to produce particles that are all between 20 and 40 nanometers in size (a nanometer is one-billionth of a meter), a range best able to elude macrophages. They also coated them with a polyethylene glycol shell, which helps them survive longer in blood circulation and enter target cells. Finally, on the inside they incorporated powerful light-absorbing, chlorine-based molecules that turn the nanoparticles into tumor killers.
In previous studies, the team found that once injected into the bloodstream, the particles are able to circulate long enough to find their way in and around tumors. And because tumors typically have a leaky, ill-formed vasculature, the particles tend to leak out at the site of cancer tissue and be picked up and internalized inside tumor cells. Once the nanoparticles are absorbed, the researchers shine near infrared light on the tumors. That light is absorbed by the chlorine-based molecules, which then excite nearby oxygen molecules, creating a highly reactive form of oxygen, known as singlet oxygen, that rips apart nearby biomolecules and kills the tumor cell.
But that’s only the start of it, Lin says. Singlet oxygen tends to rip apart tumor cells in a manner that exposes many new tumor antigens to immune cells called dendritic cells, which, like police executing a dragnet, grab the antigens and present them to T cells for closer inspection. By doing so they help the immune system mount a powerful antitumor response even in cases where there aren’t that many T-cells nearby.
In August 2016, Lin and his colleagues reported in Nature Communicationsthat when they injected a version of their nanoparticles into the bloodstream of mice with colon cancer along with a checkpoint antibody and blasted the tumors with light, the combination sparked the animals’ immune systems to destroy both the targeted colon cancer tumors as well as untreated tumors elsewhere. However, those particles also ferried a standard chemotherapeutic toxin to help kill the cancer cells. In their current study the researchers wanted to see whether the approach would work with just the immune response.
This time Lin and his colleagues worked with mice with breast cancer, another form of cancer that often doesn’t respond to current immunotherapy drugs. Again, they injected the animals with their nanoparticles along with a checkpoint antibody. But this time their nanoparticles didn’t contain any additional chemotherapeutic drug. They then blasted the tumors with infrared light, and waited for the results. And in almost every case, not only was the primary breast cancer tumor destroyed, but metastases in the lung were wiped out as well, they report in the Journal of the American Chemical Society. “We were surprised to find that without the cytotoxic agents, you can achieve the same effect,” Lin says.
“This is a well thought out approach, and the data is interesting,” says Wolchok, who was not involved in the work. The approach deserves to be followed up with human trials, he adds. Lin says such trials are likely to start soon. The Chicago team has already formed a company, called Coordination Pharmaceuticals, which has raised seed funds to launch an early stage trial in humans, likely sometime in the second half of this year.
Image caption: An artist’s conception of nanoparticles targeting tumor cells. Credit: Nicolle R. Ful/ Science Magazine.
Peer-reviewed journal article: Xiaopin Duan, Christina Chan, Nining Guo, Wenbo Han, Ralph R. Weichselbaum, and Wenbin Lin, "Photodynamic Therapy Mediated by Nontoxic Core–Shell Nanoparticles Synergizes with Immune Checkpoint Blockade To Elicit Antitumor Immunity and Antimetastatic Effect on Breast Cancer", Journal of the American Chemical Society 2016 138 (51), 16686-16695. DOI: 10.1021/jacs.6b09538