Melanoma Takes Advantage of Missing Tumor-Suppressors to Resist Immunotherapy
High genomic copy loss correlated with metastatic melanomaâ€™s ability to thwart the success of immune checkpoint inhibitors.
Missing tumor-suppressing genes are the culprit behind resistance to immune checkpoint blockade drugs, investigators recently found.
In a study published in Science Translational Medicine, the authors performed whole exome sequencing of tumor biopsies obtained from 56 patients before, during, and after treatment.
The results of the study showed that the loss of a variety of tumor-suppressing genes with influence on immune responses lead to treatment resistance to both CTLA4 and PD1 inhibitors.
The investigators sought to determine why the treatments were successful in 20% to 30% of patients—with some complete responses lasting for years—but are unsuccessful in other cancer patients.
“Is there a trivial or simple (genomic) explanation? There doesn’t seem to be one,” said co-senior author Andrew Futreal, PhD. “There’s no obvious correlation between mutations in cancer genes or other genes and immune response to 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.”
The findings indicate that analyzing the loss of blocks of the genome may provide a new predictive indicator, according to the authors.
Co-lead author Whijae Roh, who analyzed the genomic data for non-mutational effects with co-senior author Jennifer Wargo, MD, said, “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.”
Melanoma tumors containing large volumes mutational loads serve as better targets for the immune system to detect and are more susceptible to checkpoint blockades. But the authors noted that the measure is not conclusive alone.
“Combining mutational load and copy number loss could improve prediction of patient response,” Wargo said.
The investigators stratified patients in another group by whether they had high or low copy loss or high or low mutational load. The findings showed that 11 of 26 patients with high mutational load and low copy loss had a clinical benefit, compared with only 4 of 26 patients with low mutational load and high copy loss.
The participants were first treated with the immune checkpoint inhibitor ipilimumab, designed to block CTLA4 on T cells. Patients whose melanoma was unresponsive were then treated with nivolumab.
When feasible, biopsies were taken before, during, and after treatment for molecular analysis to understand response and resistance, according to the study.
The investigators analyzed tumor genomes for recurrent copy loss among 9 tumor biopsies from patients who were unresponsive to both drugs, and had a high burden of copy number loss. They found repeated loss of blocks of chromosomes 6, 10, and 11—–which harbor 12 known tumor-suppressing genes, according to the study.
An analysis of a second patient cohort confirmed the findings, with no recurrent tumor-suppressor loss found among any of the patients who achieved clinical benefit or long-term survival after treatment.
The authors noted, that their findings hinted that even if treatment with ipilimumab failed, it may prime a patient’s immune system for successful anti-PD1 treatment.
The investigators conducted an analysis of the genetic variability of a region of T cell receptors to find evidence of T cell clonality, an indicator of active T cell response.
The results of the analysis showed that among 8 patients with longitudinal samples taken before treatment with both checkpoint types, all 3 patients who responded to anti-PD1 therapy showed signs of T cell activation after treatment with anti-CTLA.
Only 1 of 5 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,” Futreal said. “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.”
Overall, investigators 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.”