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IMMUNE CHECKPOINT INHIBITORS
MAKE PROGRESS AGAINST SKIN
CANCER AND LUNG CANCER
Baylor University
Medical Center at
Dallas leads the
way with important
study contributions.
Throughout our lives, the miracle that is our human
immune system protects us from harm. Without any
effort on our part, the immune system is on constant
alert, scanning our bodies for anything out of the
ordinary and potentially dangerous, such as viral,
bacterial and fungal infections—and, yes, even cancer.
“We’ve known for many decades that the immune system plays
a role in cancer surveillance,” said Lance Cowey, MD, a medical
oncologist on the medical staff and co-medical director of Baylor
University Medical Center’s Skin Malignancy Research and
Treatment Center. “But identifying and overcoming the barriers
of the immune function against cancer has been a problem.”
On its own, the immune system can be an imperfect defense
against cancer. The problem is that cancer cells can be “smart.”
They can disguise or cloak themselves from the immune system.
The cancer takes advantage of a specific part of our immune
system that also protects us: immune checkpoints.
“It’s similar to how your coffee maker has an automatic off-
switch,” explained Dr. Cowey. “Immune checkpoints prevent
overactive immune cell function. It’s a way the immune cells
autoregulate themselves. After activation, the immune cells
can then be deactivated so that we don’t have persistent
immune activation for longer than what is needed.”
Once infections are cleared from the body, usually within
a few weeks, immune checkpoints tell the immune system
to stand down, to flip the off-switch. They keep the immune
system from rampaging out of control and attacking healthy
cells. But cancer can play a trick on the immune checkpoints
by sending out signals that tell the immune system, “These
aren’t the cancer cells you’re looking for.”
“The cancer cells take advantage of the immune
checkpoints. They take advantage of the off-switches to
circumvent normal immune activity against the cancer,” Dr.
Cowey said. Thus, the cancer hides in plain sight, suddenly
invisible to the immune system and free to do what cancer
does: uncontrollably grow, divide and spread.
What are Immune Checkpoint Inhibitors?
In just the last few years, cancer researchers have
discovered a new set of drugs that allow the immune system
to uncloak cancer cells. These drugs are called immune
checkpoint inhibitors. And they do exactly that. They inhibit
the immune checkpoints, enabling the immune system to
once again see, attack and kill the cancer cells (Figure 4).
“The immune cells are already primed to recognize the
cancer. They’ve already got the scent. All we’re doing is
releasing the hounds to attack the cancer,” Dr. Cowey said.
Figure 4. Site of action for
checkpoint inhibitors
Adapted by permission from Macmillan Publishers
Ltd: Nature Reviews Urology (13:421-431), 2016.
Melanoma Study Led to FDA Approval
Baylor University Medical Center at Dallas (BUMC) has been
a leader in developing immune checkpoint inhibitors. Led by
Dr. Cowey, BUMC was one of the largest among 137 centers
worldwide that tested 945 advanced inoperable melanoma
skin cancer patients with a combination of two checkpoint
inhibitors called nivolumab and ipilimumab. This combination
of drugs, documented by Dr. Cowey and other researchers in
the July 2015 issue of The New England Journal of Medicine*,
was approved by the US Food and Drug Administration in
September 2015 for treatment of advanced melanoma.
Both of these checkpoint inhibitors are monoclonal antibodies.
Nivolumab (Opdivo ® ) binds to the immune checkpoint protein
known as PD-1 (programmed death protein 1). Ipilimumab
(Yervoy ® ) binds to the immune checkpoint protein known
as CTLA-4 (cytotoxic T-lymphocyte–associated protein 4).
“Identification of the immune checkpoints PD-1 and CTLA-4
have been breakthroughs, as they have been important
targets for activating the immune system to have an
anticancer effect,” Dr. Cowey said.
“These drugs have been especially effective in combating
melanoma. The combination of ipilimumab and nivolumab
has set the highest standard in terms of efficacy in regards
to response rate and progression-free survival, compared to
other therapies,” Dr. Cowey said.
Next-generation trials are already under way to challenge
these standards and hopefully improve tolerability. Dr. Cowey
is accruing patients to several next-generation combination
studies evaluating checkpoint inhibitors in combination
with other immune modulators, viral therapy and
genetic-targeted therapy.