BY DEVON CARTER March 10, 2021
The immune system defends the body from viruses and
bacteria. But it’s not as successful in killing cancer on its own. Immune checkpoint inhibitors – a type
of immunotherapy – harness the immune system
to treat many types of cancers, including colorectal cancer.
“They work by blocking signals in a tumor that stop the
immune system from working,” says Scott Kopetz, M.D., Ph.D. By preventing
these signals, checkpoint inhibitors allow immune cells called T cells to
target cancer.
Pembrolizumab and nivolumab are the two immune
checkpoint inhibitors that have been most effective in treating colorectal
cancer. They’re approved by the Food and Drug Administration for patients with
a subtype of metastatic colorectal cancer called microsatellite instability-high
disease.
What is microsatellite
instability-high colorectal cancer?
Patients with microsatellite instability-high (MSI)
colorectal cancer have a lot of genetic mutations inside a tumor that fuel its
growth. Kopetz says patients may also hear the term “deficient mismatch repair”
(dMMR) to describe this subtype.
These genetic mutations are sometimes linked to a hereditary syndrome called Lynch syndrome, but
sometimes they aren’t passed down through a family and occur
sporadically.
Microsatellite instability status is determined through
a molecular profile, which is a series of tests performed on tissue that’s
removed during biopsy to learn a tumor’s genetic makeup. “Right now, this is
primarily done to help match a patient to a clinical trial,” Kopetz says.
A clearer distinction between cancer
and normal cells
To the immune system, foreign pathogens look very
different from normal cells. But the difference with cancer cells isn’t as
clear – except in microsatellite instability -high disease.
“Patients with MSI-high colorectal cancer are more
likely to have their immune systems detect the tumors are different from normal
tissue,” Kopetz says.
This helps lay the groundwork for immunotherapy to be
effective. “The good news is the immune cells often recognize the cancer cells
as different,” Kopetz says. “The barrier is the checkpoints – or the signals –
that the tumor cells put on their surface to prevent the immune cells from
attacking.”
This is where immune checkpoint inhibitors come in. They
block the signal from the tumor cells that prevents the T cells from doing
their work.
Unfortunately, only 3% of patients with metastatic
colorectal cancer have MSI-high disease.
“It’s very low,” Kopetz says. “But for the first time,
there’s a subset of patients where we can say, ‘Despite having metastatic
disease, we can cure you with immunotherapy.’” He says that hasn’t been
possible with chemotherapy and targeted therapies.
Discovering other colorectal cancer
subtypes
MD Anderson researchers are working to discover
other, less common subtypes of colorectal cancer that may also have high
mutation loads. One possible opportunity are the mutations within the POLE
gene.
“We’ve shown that tumors with POLE mutations can be
another subgroup that can be very responsive to immunotherapy and can have
complete responses as well,” Kopetz says. Efforts are underway to better
understand which patients fall into the subgroup and can benefit from these
drugs.
Research seeks to break into the tumor
microenvironment
Of the remaining 97% of patients with metastatic
colorectal cancer who don’t fall into the subset of MSI-high disease, it’s
thought they can be divided into two groups, Kopetz says. He and colleagues
have developed a tool called the consensus molecular subtype classification
system to aid in subtyping patients.
The first group is patients with CMS4 tumors. Their T
cells are activated and wanting to attack, but they can’t enter what’s called
the tumor’s microenvironment. “It’s like the tumor sets up a chain link fence
that keeps them out,” Kopetz says. When examined under a microscope, the T
cells cluster along the edges of a tumor, trying to get in.
Research is aimed at breaking down the chain link fence
to allow the T cells to enter the tumor microenvironment. Once inside, it’s
hopeful that the T cells can be effective in killing the tumor with the help of
immunotherapy.
“It’s not about activating the immune system; that's
done thanks to immunotherapy,” Kopetz says. “It's about targeting the tumor
microenvironment to get the T cells inside first.”
Overcoming the immune desert
In patients with CMS2 or CMS3 colorectal cancer, though,
the T cells show little to no activity in response to the tumor. “We refer to
it as the immune desert,” Kopetz says. When viewed under the microscope, the
immune system shows little evidence of reacting.
“The strategy is less about the tumor microenvironment –
which may still be a problem – and more focused on getting the immune system to
even recognize that there's something going on,” he says. Through MD Anderson’s Colorectal Cancer Moon Shot™,
Kopetz oversees research exploring new ways to address this challenge.
One approach is personalized vaccines. They work by
instructing the patient’s cells to produce proteins based on the mutations
driving the cancer’s growth. The immune system then searches for other cells
with the mutated proteins to clear them out.
Another opportunity is with cellular therapies
like CAR T cell therapy, T cell therapy and CAR NK cell therapy, which are being explored
through clinical trials. “With T cell therapies, we’re trying to take the few,
rare T cells that are in the tumor, expand their numbers in a lab and give them
back to the patient,” Kopetz says. “Or, we’re trying to manufacture T cells
that we design in a lab to be better equipped to attack the cancer.”
Oncolytic viruses are another research focus. A virus is
injected into the tumor and is then replicated within the cancer cells. When
the immune system targets the virus, the hope is it will also target the
mutations within the cancer cells.
“It’s a very different understanding of colorectal
cancer,” Kopetz says. “But we hope that by learning more about the differences
between these subtypes, we can direct these new treatment approaches in the
most effective way to benefit more patients.”
Request an appointment at MD
Anderson online or by calling 1-855-801-1546.
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