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1-HLA Gene May Predict If Cancer Immunotherapy Will Work - National Cancer Institute
1-HLA Gene May Predict If Cancer Immunotherapy Will Work - National Cancer Institute
1-HLA Gene May Predict If Cancer Immunotherapy Will Work - National Cancer Institute
If the findings are confirmed in further studies, doctors HLA proteins (red, purple, yellow,
could use the gene as a marker to help decide if a patient blue) display peptides (small circles)
should or shouldn’t take an immune checkpoint inhibitor, from inside the cell to help immune
said the scientist who led the study, Mary Carrington, Ph.D., cells find cancerous or infected cells.
of NCI's Center for Cancer Research. Credit: Frontiers in Immunology. Feb 2016.
https://doi.org/10.3389/fimmu.2016.00030.
That could spare many patients from getting treatments CC BY 4.0.
that don’t work for them and that can cause harsh side
effects, Dr. Carrington added. But, she cautioned, “we need
more data before [doctors would] actually use that [marker]
in the clinic.”
In their analysis of data from thousands of patients, the researchers found that people with HLA-A*03 died
sooner after immune checkpoint inhibitor treatment than people with other forms of the HLA-A gene. The
study, published December 9 in Lancet Oncology, showed that this pattern held true for different immune
checkpoint inhibitors and different types of cancer, including kidney, bladder, and skin cancer.
Timothy Chan, M.D., Ph.D., director of the Cleveland Clinic’s Center for Immunotherapy and Precision
Immuno-Oncology, called the findings “exciting.” The next step, continued Dr. Chan, who was not involved in
the study, is “to work out how [A*03] can be used most efficiently with other biomarkers” that are currently
used to predict how well checkpoint inhibitors will work.
Across the human population, “there are thousands of different forms of these HLA genes, which we call
alleles,” explained Dr. Carrington, who leads NCI’s HLA immunogenetics research.
A*03, for instance, is one of more than 2,000 alleles of HLA-A. That natural variation in HLA genes is, in part,
what makes some people more susceptible than others to certain viral infections and autoimmune diseases.
Because immune checkpoint inhibitors help immune cells find and attack cancer cells, scientists have long
suspected that variations in HLA genes may influence how well these treatments work.
Possible links between various HLA alleles and immune checkpoint inhibitor effectiveness have been studied
extensively. But, so far, A*03 is the only one that seems to work as a marker of treatment response for
multiple types of cancer and different immune checkpoint inhibitors, Dr. Carrington noted.
Among various HLA alleles, HLA-A*03 emerged as the strongest biomarker of immune checkpoint inhibitor
effectiveness. People with A*03, regardless of what kind of cancer they had, died nearly 1.5 times sooner
after starting treatment than those with a different allele, the researchers found.
When the researchers separated the data by cancer type, A*03 was linked with a shorter time to death for
people with bladder, brain (glioma), melanoma, lung, and kidney cancer. However, the impact of having A*03
was greatest in people with kidney cancer.
Among participants of four clinical studies who received an immune checkpoint inhibitor for kidney cancer,
those with A*03 didn’t live as long before their kidney cancer grew back or they died (progression-free
survival), compared with those who didn’t have the allele.
Confirming the findings in randomized clinical trials is very good evidence that A*03 is a biomarker of
immune checkpoint inhibitor effectiveness, Dr. Chan noted.
Dr. Carrington and her team also found that people with two copies of A*03 died sooner than people with
one copy of A*03 plus a copy of a different HLA-A allele (2.3 and 1.5 times sooner, respectively, than people
with no copies of A*03).
The researchers validated their findings in two independent groups of patients who had been treated with
immune checkpoint inhibitors—1,326 patients with various types of cancer treated at the Dana-Farber
Cancer Institute and 169 people with bladder cancer who had participated in an international clinical trial. In
both groups, those with A*03 died sooner after starting treatment than those without this form of the gene
(1.2 and 1.4 times sooner, respectively).
The link between A*03 and immune checkpoint inhibitor effectiveness held true regardless of a person’s age,
sex, ancestry, the type of immune checkpoint inhibitor they took, and whether they got chemotherapy at the
same time. However, the allele wasn’t linked with the outcomes of other kinds of cancer treatment.
Testing for a specific HLA allele can be fast and reliable, the researchers noted. It’s done routinely to match
donors and recipients for organ transplants, and as a way to tell who might have life-threatening allergic
reactions to certain HIV and epilepsy treatments.
And HLA genes are included in several genetic biomarker tests that are commonly given to people with
cancer, Dr. Chan noted.
But, Dr. Carrington cautioned, just because someone has A*03 doesn’t necessarily mean that they won’t
benefit from immune checkpoint inhibitors.
In all of the data the researchers looked at, there were some people with A*03 for whom immune checkpoint
inhibitor treatment worked. “It's when we look at the entire population of [people with] A*03 that we see,
overall, there's less benefit,” she said.
Ultimately, models that combine multiple biomarkers might better predict whether an immune checkpoint
inhibitor is likely to work for an individual, Dr. Chan said. “That's where this [field] is headed,” he added.
“Immunity is complex, and we know HLA is one part of the story,” he said. But many factors, from the total
number of mutations in the tumor (tumor mutational burden) to the microbes that live in the gut, also
influence how well immune checkpoint inhibitors work. And “it's clear that all these things work together,”
Dr. Chan explained.
In a recent study, he and his colleagues built a model that takes into account a person’s genetics, biology,
age, and tumor stage, among other factors, to predict whether checkpoint inhibitors are likely to work. The
combination model was more accurate than tumor mutational burden alone at predicting whether a
checkpoint inhibitor would be effective, the researchers found.
As for Dr. Carrington, her group is focused on understanding why immune checkpoint inhibitors don’t work
well for people with A*03. They are currently sifting through several plausible explanations, but none has
surfaced as the winner yet.
“We've been ruling things out one after another,” she said. But that’s the exciting part of science, she added,
figuring out a great unknown.
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Don’t Work for Everyone: HLA Gene May Explain Why was originally published by the National Cancer Institute.”
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