Melanoma is the rarest and most dangerous type of skin cancer. When melanoma
cells spread through
the lymph nodes to distant sites in the body, it is referred to as metastatic melanoma.
It's what's missing in the tumor genome, not what's mutated, that
thwarts treatment of metastatic melanoma with immune checkpoint
blockade drugs, researchers at The University of Texas MD Anderson
Cancer Center report in Science Translational Medicine
‘Absence of a variety of tumor-suppressing genes leads to resistance of metastatic melanoma treatment with both CTLA4 and PD1 inhibitors.’
Whole exome sequencing of tumor biopsies taken before, during and
after treatment of 56 patients showed that outright loss of a variety of
tumor-suppressing genes with influence on immune response leads to
resistance of treatment with both CTLA4 and PD1 inhibitors.
The team's research focuses on why these treatments help 20-30% of patients - with some complete responses that last for years -
but don't work for others. Their findings indicate that analyzing loss
of blocks of the genome could provide a new predictive indicator.
"Is there a trivial or simple (genomic) explanation? There doesn't
seem to be one," said co-senior author Andrew Futreal, professor
and chair of Genomic Medicine and co-leader of MD Anderson's Moon Shots
Program™. "There's no obvious correlation between mutations in cancer
genes or other genes and immune response in these patients."
"There are, however, pretty strong genomic copy loss correlates of
resistance to sequential checkpoint blockade that also pan out for
single-agent treatment," Futreal said. Doctoral candidate Whijae Roh,
co-lead author, Futreal, and co-senior author Jennifer Wargo,
associate professor of Surgical Oncology and Genomic Medicine, and
colleagues analyzed the genomic data for non-mutational effects.
"We found a higher burden of copy number loss correlated to response
to immune checkpoint blockade and to lower immune scores, a measure of
immune activation in the tumor's microenvironment," said Roh, a graduate
student in the University of Texas MD Anderson UTHealth Graduate School
of Biomedical Sciences. "We also found copy loss has an effect that is
independent of mutational load in the tumors."
Mutational load + copy loss tells a story
Melanoma tumors with larger volumes of genetic alterations, called
mutational load, provide more targets for the immune system to detect
and are more susceptible to checkpoint blockade, although that measure
is not conclusive alone. "Combining mutational load and copy number loss
could improve prediction of patient response," Wargo said.
When the team stratified patients in another data set of patients by
whether they had high or low copy loss or high or low mutational load,
they found that 11 of 26 patients with high mutational load and low copy
loss had a clinical benefit, while only four or 26 with low mutational
load and high copy loss benefited from treatment.
In the trial, patients were treated first with the immune checkpoint
inhibitor ipilimumab, which blocks a brake called CTLA4 on T cells, the
immune system's specialized warriors, freeing them to attack.
Patients whose melanoma did not react then went on to anti-PD1
treatment (nivolumab), which blocks a second checkpoint on T cells.
Biopsies were taken, when feasible, before, during and after treatment
for molecular analysis to understand response and resistance.
To better understand the mechanisms at work, the team analyzed tumor
genomes for recurrent copy loss among nine tumor biopsies from patients
who did not respond to either drug and had high burden of copy number
loss. They found repeated loss of blocks of chromosomes six, 10 and 11,
which harbor 13 known tumor-suppressing genes.
Analysis of a second cohort of patients confirmed the findings, with
no recurrent tumor-suppressor loss found among any of the patients who
had a clinical benefit or long-term survival after treatment.
Ipilimumab sometimes wins when it fails
The researchers also found a hint that treatment with ipilimumab,
even if it fails, might prime the patient's immune system for successful
The team analyzed the genetic variability of a region of the T cell
receptors, a feature of T cells that allows them to identify, attack and
remember an antigen target found on an abnormal cell or an invading
microbe. They looked for evidence of T cell "clonality," an indicator of
active T cell response.
Among eight patients with longitudinal samples taken before
treatment with both checkpoint types, all three who responded to
anti-PD1 therapy had shown signs of T cell activation after anti-CTLA
treatment. Only one of the five non-responders had similar indicators
of T cell clonality.
"That's evidence that anti-CTLA4 in some cases primes T cells for
the next step, anti-PD1 immunotherapy. It's well known that if you don't
have T cells in the tumor, anti-PD1 won't do anything, it doesn't bring
T cells into the tumor," Futreal says.
Overall, they found that T cell clonality predicts response to PD1 blockade but not to CTLA-4 blockade.
"Developing an assay to predict response will take an integrated
analysis, thinking about genomic signatures and pathways, to understand
the patient when you start therapy and what happens as they begin to
receive therapy," Wargo said. "Changes from pretreatment to on-therapy
activity will be important as well."
APOLLO tracks response over time
The Science Translational Medicine
paper is the third set of
findings either published or presented at scientific meetings by the
team, which is led by Futreal and Wargo, who also is co-leader of the
Melanoma Moon Shot™.
Immune-monitoring analysis showed that presence of immune
infiltrates in a tumor after anti-PD1 treatment begins is a strong
predictor of success. They also presented evidence that the diversity
and composition of a patient's gut bacteria also affects response to
The serial biopsy approach is a hallmark of the Adaptive
Patient-Oriented Longitudinal Learning and Optimization™ (APOLLO)
platform of the Moon Shots Program™, co-led by Futreal that
systematically gathers samples and data to understand tumor response and
resistance to treatment over time.
The Moon Shots Program™ is designed to reduce cancer deaths by
accelerating development of therapies, prevention and early detection
from scientific discoveries.