surface. One of his most important findings was to locate a receptor called CD28
that acts like a gas pedal. When it gets
engaged, it is one of two key signals—in
addition to a receptor that actually locks
onto a tumor cell and functions somewhat
like an ignition switch—that a T cell needs
to initiate an attack.
Even when those switches were flipped
to the “on” position, however, such attacks
were often short-lived and sometimes
failed to start up at all. By 1992, Allison
thought there might be a third switch. The
most likely candidate: C TLA- 4, a mysterious receptor sometimes spotted on T cells.
But both Allison and Bluestone, the UCSF
immunologist, found that this molecule
behaved unexpectedly. When proteins
bound to it, it didn’t turn a T cell on—it
turned it o;. These molecular brakes were
Scientists subsequently demonstrated
why evolution might have favored checkpoints. When they created mice lacking
CTLA- 4, their T cells ended up attacking
their own bodies after an infection. Without an o; switch, the mice “died within a
few weeks, of massive autoimmune disease,” Bluestone recalls.
Bluestone initially saw the chance to
develop new types of immune-suppressing
drugs—say, for organ transplant patients.
But Allison saw a different possibility.
Releasing these brakes might strengthen
the immune system’s response against
cancer. One of Allison’s graduate students
had already developed an antibody able
to stick to a T cell’s CTLA- 4 receptors,
“;WE WERE; JUST
essentially jamming the switch. Allison instructed a postdoc to
inject the antibody into mice riddled with tumors. The results,
he recalls, “were spectacular.”
“The tumors were cured,” Allison says. “I mean, it was 100
percent and zero percent—no statistics necessary.”
The drug, the first of the checkpoint inhibitors, would become
known as ipilimumab or Yervoy, and it is now sold by Bristol-Myers Squibb, a pharmaceutical company headquartered in
Manhattan. Human studies began around 2000 on 14 patients
stricken with metastatic melanoma, who were steeling themselves for their finals days in hospice. But after the trial began,
three saw their tumors shrink. Allison, who moved to New York
City’s Memorial Sloan Kettering in 2004 to be closer to the trials,
soon met one of the patients his drug had saved. Sharon Belvin
was in her 20s, and had just finished college and gotten married,
when metastatic melanomas appeared in her lungs, liver, and
brain. She was terminal by the time her physician enrolled her
in the first phase II clinical trial. The day Allison met her, she’d
been in remission for a year.
“She hugged me,” Allison recalls. “Her husband hugged me,
and her mother and father were there, and they all hugged me.
It was just sobbing, and everybody was really happy. I walked to
my o;ce and I had a lot to think about. I cried all the way there.”
Allison says by that time he was aware of his drug’s limitations. It didn’t help everyone, and it didn’t work in most cancers.
And if he needed a reminder of the stakes, it came in 2005, when
Allison’s brother succumbed to prostate cancer after eight years.
The same year, doctors found early-stage cancer in Allison’s own
prostate. He had surgery rather than chance drug treatment.
As soon as cancer researchers learned that Yervoy worked on
some previously incurable patients but not on others, many asked
the obvious question: was it possible the body had more than one
checkpoint? Another molecule, called PD- 1, was quickly identified and successfully targeted with checkpoint inhibitors. Allison’s
Yervoy was approved in 2011 by the U.S. Food and Drug Administration for patients with melanoma. Three years later the FDA
approved Merck’s PD- 1 inhibitor pembrolizumab (Keytruda) and
a similar drug, also from Bristol-Myers Squibb, called nivolumab
(Opdivo). One or both have since been approved to treat some
types of lung cancer, kidney cancer, and Hodgkin’s lymphoma,
creating the most important new class of cancer drugs in a century.
The day I arrived at MD Anderson to tour the platform, an Argentinean immunologist, Luis Vence, greeted me in a fluorescent-lit
hallway. Our first stop was a lab where he swung open the door CO