The discovery of a cell protein reveals a new way of harnessing the power of the
immune system to fight cancer. Immune checkpoint inhibitors are now showing
promise against a wide variety of cancers.
Background:
The notion that the human immune system can be enlisted to fight cancer has a
long history in medical science, dating back to the beginning of the 20th century.
For much of that period, researchers sought ways of strengthening the natural immune
response to cancer through the development of therapeutic cancer vaccines
and other immune-stimulatory techniques.
As this work was under way, a smaller group of scientists focused on the
means by which cancer cells protect themselves from an immune system attack.
This latter approach gained momentum in the 1990s, with discoveries about the
function of T cell co-receptors in regulating the immune response to disease. It
had previously been thought that co-receptors played a purely stimulatory role,
inciting T cells to mobilize an immune system assault on infected or malignant
cells. Researchers later discovered that some co-receptors act as a brake on the
immune response, protecting the body from autoimmune disease. This discovery
suggested that blocking such inhibitory co-receptors with drug agents could
unleash an immune system attack on tumor cells.
The discovery of PD-L1:
In 2000, Dana-Farber Cancer Institute’s Gordon Freeman, PhD, and his
colleagues published a study announcing the discovery of the protein PD-L1
(programmed cell death 1 ligand 1) on normal cells. The researchers found that
PD-L1 exerts an inhibitory effect on T cells by binding to the T cell co-receptor
PD-1, thereby signaling the T cell not to instigate an immune system attack.
A year later, Freeman and his colleagues published a follow-up study, reporting
that PD-L1 appears not only on some normal cells but on certain cancer cells as
well. The implication was that an agent that blocks PD-L1 (or a related ligand,
PD-L2) could release the brakes on an immune system attack on the cancer.
The discovery prompted pharmaceutical companies to pursue the development
of drug agents that block PD-1, PD-L1, or PD-L2. Several of these drugs –
known as immune checkpoint inhibitors – have recently received Food and Drug
Administration (FDA) approval for treating certain types of cancer and are being
tested in a variety of other cancers.
Early results of clinical testing:
Dana-Farber investigators are now studying which tumor types respond to
immune checkpoint inhibitors, the mechanism by which such inhibitors work,
and how they can be improved. In early-stage clinical trials, immune checkpoint
inhibitors are producing striking results in some cancers. In a phase 1 trial
led by Dana-Farber investigators Margaret Shipp, MD, and Phillippe Armand,
MD, PhD, investigators tested the PD-1 blocker nivolumab in 23 patients with
Hodgkin lymphoma who had exhausted numerous other treatment options,
often including a stem-cell transplant. Some 87 percent of the participants had
experienced a full or partial remission of the disease. The majority of them were
still doing well a year and a half after treatment, when the results were published
in the New England Journal of Medicine. The findings prompted the FDA to
designate nivolumab a “breakthrough therapy” for relapsed Hodgkin lymphoma
and a multinational phase 2 trial is now under way.
In glioblastoma, researchers led by Dana-Farber’s David Reardon, MD, and
Gordon Freeman tested a PD-1-targeting antibody in mice with the cancer. More
than half the mice that received the agent were long-term survivors, showing
no evidence of tumor in their brain after 50 days. 25-30 percent of those that
received antibodies against PD-L1 and CTLA-4 were considered cured. On the
strength of these results, Dana-Farber investigators have opened three clinical
trials of these agents.
In a phase 1 trial of a PD-L1 inhibitor in patients with bladder cancer, DanaFarber’s
Joaquim Bellmunt, MD, PhD, and his colleagues reported that, after
12 weeks of treatment, there was tumor shrinkage in 52 percent of the patients
whose T cells have high levels of PD-L1 prior to treatment. Although more than
half of the participants experienced adverse side effects to the drug, known as
MPDL3280A, none of them were particularly severe.
Investigators at the Dana-Farber/Brigham and Women’s Cancer Center led by
Toni Choueiri, MD, opened their first clinical trial of a PD-1 and PD-L1 blocker
for patients with kidney cancer five years ago. Although the results haven’t been
published yet, about 20 percent of the trial participants, many with tumors that
defied previous treatments, responded to the checkpoint inhibitor. Choueiri and
Sabina Signoretti, MD, are analyzing tumor tissue for biological signs that indicate
which patients are likely to respond best to the treatment.
Dana-Farber researcher Peter Hammerman, MD, PhD, and his associates are
studying the genetics of lung cancer to determine if certain mutations render
tumors more susceptible to immune checkpoint inhibitors. David Barbie, MD, is
studying whether variations in the immune system from one person to another
affect individuals’ cancer-fighting ability. The researchers also are exploring
whether as-yet undiscovered checkpoint proteins play a role in turning off an immune
system attack and could be targeted in future studies.
One of the hallmarks of immune checkpoint inhibitors has been the durability
of the cancer remissions they produce unlike some chemotherapy and targeted
agents that lose potency as cancer cells develop new genetic mutations.
On the strength of the results in early clinical trials, investigators plan to test immune
checkpoint inhibitors against additional types of cancers. While these therapies
are likely to be more effective against some malignancies than others, immune
checkpoint blockade is rapidly becoming a fixture of the medical arsenal for cancer.