The search for drugs that spur the immune system to fight tumors has led scientists to experiment with tiny nanoparticles. These microscopic miracles, smaller than the width of a human hair, might help the body’s own immune system fight tumors. In the study they conducted with mice, the nanoparticle-based therapy not only wiped out the originally targeted breast cancer tumors but metastases in other parts of the body as well. The researchers say the experiment went so well that human clinical trials could begin within the next several months.
Blinded T Cells
Our body naturally contains special cells called Immune sentries, known as T cells. Normally, they are helping us out, constantly on the prowl for suspicious-looking targets, such as bacterial invaders and potential tumor cells. If they recognize one, they sound the alarm, prompting other immune cells to mount a larger response.
However, it is possible for the T cells’ alarm to be muted by so-called immune checkpoints. Immune checkpoint molecules are other proteins on the surface of normal cells. These molecules are often overexpressed (produced in abundance) by tumor cells. When these molecules cover the normal cells, they essentially blind them, blocking the immune response to prevent a harmful autoimmune reaction to normal tissue. Therefore, this halts the immune system’s search and destroys work.
Current Solutions
At the moment, the only way to overcome this problem is by blocking these overexpressed checkpoint molecules. To do so, pharmaceutical companies have developed a number of different antibody proteins that do the job. These antibody proteins block the checkpoint molecules and, as a result, enable the immune system to target tumors as they should.
This method works well in cases where there are lots of T cells in the vicinity of a tumor. It also works well in situations where tumor cells have undergone large numbers of mutations, which creates additional targets for T cells (in other words, when the T cells wake up and realize how much work they have to do, they freak out into action). In both of these cases, T cells will signal a full-fledged immune response to the cancer, thus adding extra years to patients’ lives. Unfortunately, these cases account for only 20-30 percent of all cancer patients who take such immunotherapy drugs.
Jedd Wolchok, a cancer immunotherapy expert at the Memorial Sloan Kettering Cancer Center in New York City, says that the other 70-80 percent of the time, even when the checkpoint molecules are blocked, there are too few active T cells around to even sound the immune alarm. Or, the tumors don’t display enough of the T cells’ targets, so-called tumor antigens, on their surface.
Rare Cases
Wenbin Lin, a chemist at the University of Chicago in Illinois and one of the authors of the study, got his inspiration from a phenomenon that occurs in patients receiving radiation therapy. Oncologists are familiar with this rare occurrence, so it has been happening for quite some time now. What happens is when the patient receives the 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.
Until recently, they had no idea why this would happen. But now, researchers believe that it’s because irradiation sometimes kills tumor cells in a manner that exposes new antigens to T cells, preparing them to target other tumor cells that carry those antigens as well. Lin figured that maybe he could use nontoxic nanoparticles to sensitize the immune system in a similar way.
Future Solutions
There were obstacles involved, of course. For one, how would he get the nanoparticles past the immune system? If he didn’t make them small enough, cells in the blood called macrophages would gobble them up. Any big particles are easily detected and taken care of by the macrophages. There’s also the challenge with the blood proteins. They coat particles to facilitate their uptake.
Keeping all these obstacles into consideration, Lin’s team devised the following method:
- They produced particles that are all between 20 and 40 nanometers in size (a nanometer is one-billionth of a meter). They found this to be the optimal range for eluding macrophages.
- Then, they coated them with a polyethylene glycol shell. This serves as a shield, helping them to survive longer in blood circulation and enter target cells.
- Finally, on the inside, they incorporated powerful light-absorbing, chlorine-based molecules. These molecules turn the nanoparticles into tumor killers!
How It Works:
- They injected the nanoparticles into the bloodstream.
- The particles circulate until they find their way in and around tumors. Since 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.
- As a bonus, singlet oxygen tends to rip apart tumor cells in a manner that exposes many new tumor antigens to immune cells called dendritic cells. Dendritic cells behave like police executing a dragnet – they grab the antigens and present them to T cells for closer inspection.
- When this happens, it helps the immune system mount a powerful antitumor response even in cases where there aren’t that many T-cells nearby.
The Experiments
They conducted two separate experiments on mice. In both of them, they injected the animals with their nanoparticles along with a checkpoint antibody. The difference was, in one of the experiments, the particles also ferried a standard chemotherapeutic toxin (drug) to help kill the cancer cells, and in the other experiment, they didn’t. Both of the experiments were successful in destroying the tumors.
Lin admits:
“We were surprised to find that without the cytotoxic agents, you can achieve the same effect.”
The study involving the use of a standard chemotherapeutic toxin was reported in Nature Communications.
The study of nanoparticles that didn’t contain any additional chemotherapeutic drug was reported in the Journal of the American Chemical Society.
