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Now medications have been developed to bypass
those checkpoints. The first such medication to
undergo testing was ipilimumab, an antibody to
the inhibitory receptor CTLA4. Ipilimumab sits on
the surface of immune T cells and blocks CTLA4’s
activity, allowing the T cells to attack tumors. Soon
after its success, scientists also achieved favorable results with antibodies that block either PD-1,
expressed on immune cells, or its suppressor,
PD-L1, found on tumors and some immune cells.
Today, four such checkpoint inhibitor antibodies
are on the market—nivolumab (Opdivo) and pembrolizumab (Keytruda) against PD-1; atezolizumab
(Tecentriq) against PD-L1; and ipilimumab (Yervoy)
against CTLA4—and other potential checkpoint
targets are being actively pursued.
Checkpoint inhibitors have already changed
cancer treatment, says David Kaufman, executive
director of translational immuno-oncology and lead
for oncology clinical research at Merck Research
Laboratories in North Wales, Pennsylvania, which
makes the checkpoint inhibitor pembrolizumab. “What it’s done is
displace chemotherapy in many settings where chemotherapy was
either the only option or the best of a handful of less-than-ideal
solutions,” he says.
Checkpoint receptors are just one type of immune molecule
that scientists hope to take advantage of. “Almost anything on
the surface of a T cell is now a potential target for activating
the immune response,” says Korman, adding that there are also
molecules on T cells that, when bound, shore up the immune
response. These molecules are called “costimulatory receptors,”
and companies are already testing whether binding and activating
them with antibodies could improve immune activity.
Diferent patients, diferent responses
For some patients, treatment with checkpoint inhibitors can
destroy cancer, or at least keep it in check, leading to “a new
détente between the tumor and the immune system,” says
Kaufman. Around 20% of all cancers respond to this type of
treatment, he estimates. Those tend to be the people who already
have cancer-targeted T cells waiting in their tumors before
they even start immunotherapy. All their T cells need is for the
checkpoint inhibitors to unfetter them. But for other patients,
checkpoint inhibitors don’t work.
There are probably multiple reasons for the different response
patterns, and researchers at Merck and elsewhere are trying to
understand them. It might be that certain tumors have antigens—
the molecules immune cells recognize as foreign or dangerous—
that are hard for the immune system to identify, Kaufman
explains. Or perhaps T cells are present but are unable to reach
the cancer cells, he adds.
Another issue is that sometimes patients respond to checkpoint
inhibitors at first, then develop resistance. Researchers are just
starting to figure out why that might be, says Kaufman. In some
cases, the tumors seem to change, making themselves resistant
to the attacking molecules produced by T cells. Or they may
undergo mutations rendering them invisible to those T cells, and
thus evade attack.
For those unlucky patients who don’t respond to checkpoint
inhibitors, others are working on cancer vaccines as a way to
wake up the immune system and bring those T-cell “soldiers”
to the tumor site. The idea, explains Elizabeth Jaffee of Johns
Hopkins University School of Medicine in Baltimore, Maryland,
is to generate new T cells specific to the cancer, so follow-up
treatment with checkpoint inhibitors can set them to work.
She is now planning for trials with a fast genetic-sequencing
technology that defines unique mutations in tumor cells—called
“neoantigens”—to create tailored vaccines.
Riding in CARs
Checkpoint inhibitors may also work in combination with cell-based therapies. Normally, the body eliminates T cells that would
attack its own, “self-” tissues and cause autoimmune disease,
leaving only immune cells that attack anything “nonself.” That
gives cancer an advantage, since it’s also a self-tissue. The idea
of CAR T-cell therapy, explains Brentjens, is to “re-educate”
certain T cells to identify the tumor as nonself.
T cells use T-cell receptors (TCRs) to identify antigens.
Researchers add a gene to a T cell to manufacture modified
TCRs, or CARs, on T-cell surfaces. These specialized receptors
contain an antibody-like part that binds to a specific protein
(antigen) on a cancer cell. Further inside the cell, the CARs have
a domain that mimics the signals activated by antigen-attached
or “bound” TCRs. A transmembrane domain, and a flexible hinge
that allows the antigen-binding portion to reach its target, round
out the chimeric protein. Researchers frequently use lentiviruses
or retroviruses to deliver the genetic payload to the T cells. Once
inside a patient, when the CAR-bearing T cell binds a cancer cell,
it should respond as if it’s seen an invader and attack.
So far, CAR T-cell trials have focused primarily on blood
cancers. All B cells in the blood, including any cancerous ones,
express a marker called “CD19,” so researchers designed CARs
that bind to it. In a recent trial, Novartis announced that 89%
of children with acute lymphoid leukemia were alive after six
months. Without the treatment, one would expect that I L L U
are becoming the
— John Maher, an
clinician at King’s