Right now, the only way to find out if the T cells are attacking the
cancer is to wait to see if the tumors shrink, but that can take
months. And even when a treatment is working, some tumors may appear to
get bigger for a while - a result of inflammation.
So a temporarily
enlarged tumor doesn't necessarily mean treatment has failed. Even if
clinicians are sure treatment has failed, they don't know why. Did the T
cells not reach the tumor? Or did the T cells get to the tumor but fail
in their attack?
‘A way to visualize and monitor the behavior of immune cells used to treat cancer patients has been demonstrated by Stanford researchers.’
A way to visualize and
monitor the behavior of immune cells used to treat cancer patients has been demonstrated by a study led by researchers at the Stanford University School of
The new technique allows researchers to see where immunotherapy
cells go as they hunt down tumors in the human body. The imaging
technique also reveals whether the immune cells, called T cells, have
found a tumor; how many T cells have arrived at the tumor; and whether
the T cells are alive.
The ability to see whether T cells are attacking tumors is useful
both for clinicians trying to learn if a treatment is working in an
individual cancer patient and also for researchers trying to understand
why immunotherapy doesn't always work.
A paper describing the work will be published online in Science Translational Medicine
The senior author is Sanjiv "Sam" Gambhir, professor and chair
of radiology at Stanford. Lead authorship of the study is shared by
former Stanford postdoctoral scholars Khun Keu, Timothy Witney
and Shahriar Yaghoubi.
"We can now watch anywhere in your body where those T cells may be,"
said Gambhir, who holds the Virginia and D.K. Ludwig Professorship in
Cancer Research. "This is the first demonstration in humans of actually
noninvasively imaging the immune system in action with reporter gene
technology. It's never been done before in a living human, and without
the need to remove any tissue."
The work was done in patients with a type of deadly brain cancer
called glioblastoma, but the groundbreaking technique could be used to
track immune cells targeting any kind of cancer, Gambhir said.
The limitations of immunotherapy
In one form of standard immunotherapy, a medical team harvests T
cells from a cancer patient's blood and genetically engineers them to do
a better job of hunting down and killing the patient's cancer cells.
Such immunotherapy sometimes works, but most often does not. But it's
hard for clinicians to tell when it's not working, and challenging to
know why it's not.
"That's the problem," Gambhir said. "How do you know whether the T cells are doing their job or not? There's no way to tell."
"We are shooting blind," said Gambhir, who is also the director of
the Canary Center at Stanford for Cancer Early Detection. "There are no
real tools to see if treatment is working."
It can take a medical team several months to determine if
immunotherapy is working. If it hasn't, the cancer may have spread or
become more resistant in the meantime, greatly increasing the likelihood
the patient will die.
Releasing the hounds
Ten years ago, Gambhir and his lab began looking for ways to find
out what the immune cells do once they are released back into the
patient's bloodstream to hunt down cancer cells.
The researchers first engineered T cells to better recognize the
patient's cancer cells. Later, they added a "reporter gene" to the T
cells. This gene made a protein they could see with a positron emission
The tagged T cells are a little like bloodhounds that bay loudly as
they chase down their prey. The baying tells the dogs' human handlers
where both the bloodhounds and the prey are. In the same way, the
researchers could tell when T cells were near their prey - a tumor -
because they could see the protein products of the reporter genes
PET scans showing the T cells' locations tell researchers how many T
cells have reached a tumor - whether it's 6 million cells or 50
million - and whether the cells are alive.
"And you can come back and redo the imaging after a few days, weeks
or months," said Gambhir. Repetition of the scan provides a timeline of T
One thing the new technique cannot do is tell researchers whether
the T cells are actually attached to tumor cells. But that's coming,
"Right now, the reporter gene is always on," he said. "But we could
change the reporter gene so it only comes on after it latches onto the
tumor cell and kills it." That approach works in mice, but isn't quite
ready for human trials, he said.
The new T cell imaging technology can also reveal, indirectly, where
other unsuspected tumors are. "In one patient," said Gambhir, "the T
cells went to the tumor in the brain, as expected. But some of the T
cells wandered away to another area of the brain." Even though the
second tumor had been invisible to standard imaging, the "bright" T
cells in the PET scan revealed its presence.
But the biggest surprise, said Gambhir, is that the technique worked
at all. "Some people are going to say, 'This is not possible; how did
they get this to work?'"
Part of it is chance and part of it is a lot of his team's prior
research efforts, he said, estimating that his lab has produced 50
papers over the last 15 years in the quest to make the T cell imaging
technology work, first in animals, and, now, finally, in humans.
What T cell imaging means for patients
Glioblastoma is a particularly intractable cancer for which
immunotherapies have a long way to go, said Gambhir. In all of the cases
in the study, the team was able to visualize the T cells. "But in every
single case, the patient still died," Gambhir said. "So the question
is, what is going wrong? Is it that the T cells just are not surviving
long at the tumor site? Is the tumor too aggressive? Do the T cells kill
some of the tumor cells but the rest go on?"
For glioblastoma patients, said Gambhir, the new technique will
allow researchers to see immunotherapies in action and thus be better
able to understand, and hopefully fix, things that go wrong with them.
The work is an example of Stanford Medicine's focus on precision
health, the goal of which is to anticipate and prevent disease in the
healthy and precisely diagnose and treat disease in the ill.