Team connects genetic variant to poor outcomes after certain cancer treatment

Scientists have identified a genetic variant that can predict whether immunotherapy drugs called immune checkpoint inhibitors, used to treat cancer, might fail in certain patients.

The team’s findings, which appear in Lancet Oncology, point to HLA-A*03, an allele (a form of a gene) found on chromosome 6 of human DNA. The presence of HLA-A*03 in cancer patients’ DNA was associated with ineffective immune checkpoint inhibition therapy and lower survival rates in the patient population overall, despite treatment.

“[HLA-A*03] appeared to associate with poor response to immune checkpoint inhibition, and it appeared to do so across tumor types. Not all were significant, but they were all trending in a bad direction,” said Mary Carrington, Ph.D., senior investigator on the study and the director of the Basic Science Program at Frederick National Laboratory.

The allele’s connection with these poor responses could make it a useful screening marker to determine whether a patient should receive immune checkpoint inhibitors. It remained a relevant predictor even after the team accounted for other variables.

Performing genetic sequencing to determine whether a patient carries HLA-A*03 wouldn’t be cumbersome in most medical settings, said Carrington and her colleagues—a team from government, industry, hospitals, and cancer centers who collaborated on the paper.

Immune checkpoint inhibitors are a class of therapy that blocks some of the human body’s natural safeguards against the immune system over-responding in a way that potentially results in autoimmunity. However, these safeguards can also prevent the immune system from attacking cancer cells. By unshackling the immune system, the treatment lets cell-killing white blood cells recognize and kill tumor cells they’re otherwise prevented from targeting.

The exact means by which the presence of HLA-A*03 affects the therapy isn’t yet clear, but it may be connected to the allele’s role in the body. HLA genes, such as HLA-A*03, contain a genetic recipe that the body uses to produce proteins integral to the immune system’s function.

“The real need [next] is to figure out what the functional basis is for A*03—why people are responding relatively poorly to immune checkpoint inhibitors,” Carrington said.

‘That set us off’

The team first identified the allele’s connection in Memorial Sloan Kettering Cancer Center’s large MSK-IMPACT data set through an analysis of five different cancers and a combined group of more than 20 other cancers. Across cancer types, patients with HLA-A*03 who received immune checkpoint inhibitors fared worse than those without HLA-A*03 after immune checkpoint inhibition therapy. 

“Cancers are so heterogeneous in nature that finding a common factor that seems to have a global impact across them is intriguing,” said Mathias Viard, Ph.D., co-first author on the study and a scientist on Carrington’s team.

“It said that this is not something that’s specific to a certain cancer. It might be stronger in certain cancers. … I think that really set us off and made us think, ‘Okay, there could be something here. We really need to pin it down,’” Carrington said.

Even more striking, patients with two copies of the allele—one from each parent—had poorer responses and survival than those with only one copy—inherited from just one parent. That suggests that more HLA-A*03 results in poorer outcomes.

Meanwhile, there was no connection between HLA-A*03 and response in patients who received a therapy other than immune checkpoint inhibition, suggesting the allele’s effect is specific to this class of treatment.

The team expanded its analysis to data sets from seven other trials. The results were similar in each, adding more weight to the connection. In total, the study spanned samples from nearly 3,400 patients with various cancers that had been treated with immune checkpoint inhibitors, along with samples from another almost 11,000 patients who weren’t treated with immune checkpoint inhibitors.

Now, the focus turns to better understanding the connection and checking other HLA alleles.

“Maybe it’s just a stronger deleterious effect in people with A*03, but that mechanism may be occurring to some extent with other alleles as well, but it’s just not as strong as A*03. I think we need to really figure that out,” Carrington said.

Following the evidence

The study sprung from conversations between Carrington; clinician James Gulley, M.D., Ph.D., at the National Cancer Institute; and one of Carrington’s former fellows, Vivek Naranbhai, M.D., Ph.D., D.Phil, at Dana-Farber Cancer Institute and Massachusetts General Hospital. They applied for and received NCI FLEX funding to investigate effects potentially instigated by HLA. 

“A lot of lines of evidence had indicated that HLA is really important in determining response to immune checkpoint inhibition,” Carrington said. “Since we work so heavily in this area, we thought … we would be able to analyze effects of HLA in these different tumor types.”

Their study underscores the idea that a person’s genes may influence the success of immune checkpoint inhibition therapy, and the evidence emphasizes the importance of the HLA genes’ role in immunity and cancer. The findings improve understanding and offer an opportunity for additional studies—and better approaches to treatment in the clinic.

“Any further insight into understanding the roots of the negative impact of HLA A*03 will help in improving treatment for a variety of cancers,” Viard said.

Collaborating parties on the study were Frederick National Laboratory, NCI, Massachusetts General Hospital, Dana-Farber Cancer Institute, EMD Serono Research and Development Institute, Bristol-Myers-Squibb, and Pfizer.