St. Joseph’s College Jakhama
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. The search for drugs that urge 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 over expressed checkpoint molecules and enable the immune system to target tumors. In some 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. But 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.
Researchers are trying to 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 researcher 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. 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.
Recent report says that when a version of their nanoparticles injected 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.
Researcher 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 found that without the cytotoxic agents, they can achieve the same effect.
Researchers are trying to followed up this method with human trial soon. With this cancer immunotherapy can add extra years to patients’ lives.