这一次，林和他的同事对患有乳腺癌的老鼠进行了研究。乳腺癌是另一种癌症，通常对目前的免疫治疗药物没有反应。再次，他们将纳米颗粒和检查点抗体注射到动物体内。但这一次，他们的纳米颗粒不包含任何额外的化疗药物。然后他们用红外光照射肿瘤，等待结果。他们在《美国化学学会杂志》(Journal
of the American Chemical
Society)上报告说，在几乎所有病例中，不仅原发性乳腺癌肿瘤被摧毁，肺部转移也被清除。“我们惊讶地发现，没有细胞毒性药物，也能达到同样的效果，”林说。
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 Communications that
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.
