Absent tumor-suppressors allow melanoma to thwart immunotherapy

The University of Texas MD Anderson Cancer Center Mar 07, 2017

Serial treatment, biopsies, analysis also show anti–CTLA4 can prime T cells for anti–PD1 success.
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 the journal Science Translational Medicine.

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 percent 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.

Doctoral candidate Whijae Roh, co–lead author, Futreal, and co–senior author Jennifer Wargo, MD, 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.”

“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 4 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 9 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 6, 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.

The researchers also found a hint that treatment with ipilimumab, even if it fails, might prime the patient’s immune system for successful anti–PD1 treatment.

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.

T cell clonality predicts response to PD1 blockade but not to CTLA-4 blockade.
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