A recent study pinpoints loss of IFNγ signaling as one reason why many patients do not respond to the CTLA-4 inhibitor ipilimumab. Analyzing whole-exome tumor sequencing data from 16 patients with melanoma, the researchers found multiple copy-number alterations that led to the loss of key IFNγ pathway genes in 12 ipilimumab nonresponders. Mice bearing melanoma tumors that lacked one of these genes, IFNGR1, also had an impaired response to anti–CTLA-4 therapy and significantly reduced overall survival, compared with their counterparts whose tumors had intact IFNGR1.

For some patients with melanoma, treatment with the CTLA-4 inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) provides a significant survival benefit. However, about 80% of patients do not respond to this immunotherapy, and a recent study offers one reason why: loss of IFNγ signaling.

Senior author Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues previously showed that treatment with ipilimumab increased T cells' production of IFNγ, a key cytokine that inhibits tumor cell growth in addition to promoting apoptosis and antitumor immune responses. This led them to theorize that defects in IFNγ pathway genes might make tumor cells resistant to ipilimumab.

Sharma's team evaluated whole-exome tumor sequencing data from 16 patients with melanoma, four of whom responded to ipilimumab and 12 of whom did not. They uncovered 184 somatic mutations of IFNγ pathway genes in the nonresponders, but just four mutations in the responders. Most were copy-number alterations, accounting for the dramatic difference. Notably, important IFNγ pathway genes—including IFNGR1, IFNGR2, IRF1, and JAK2—were lost in nonresponders, while SOCS1 and PIAS4, which inhibit IFNγ signaling, were both amplified.

A subsequent analysis of data from 367 patients with metastatic melanoma, collected as part of The Cancer Genome Atlas, revealed that patients with wild-type tumors lived longer than those with copy-number alterations in IFNγ pathway genes—48.2 months and 40 months, respectively.

When the researchers knocked out IFNGR1 in a mouse melanoma cell line, then treated the cells with IFNγ, they observed that the loss of IFNGR1 halted IFNγ-mediated apoptosis and suppression of cell growth. Meanwhile, mice whose melanoma tumors lacked IFNGR1 had an impaired response to anti–CTLA-4 therapy and significantly reduced overall survival, compared with their counterparts bearing tumors with intact IFNGR1.

This study demonstrates the importance of tumor genomic data as prognostic information for patients selected to receive immune checkpoint therapy, Sharma says. Ipilimumab resistance could potentially be countered by combining the drug with pembrolizumab (Keytruda; Merck), a PD-1 inhibitor also approved for melanoma, she adds. However, a study headed by Antoni Ribas, MD, PhD, of the University of California, Los Angeles, found that two of four patients who initially responded to pembrolizumab developed resistance as a result of acquiring JAK1 and JAK2 mutations that led to blunted IFNγ signaling. As such, Sharma thinks combinations of ipilimumab with an angiogenesis inhibitor or with radiation are also worth exploring.

“This was just a retrospective analysis of a small number of patients,” she cautions. “We're in the process of designing prospective studies to try to confirm our data in a more robust fashion. After that, we can make decisions about how these findings might affect patient care.”

Ribas considers that Sharma's study “adds to our knowledge of resistance mechanisms” in immune checkpoint therapy, “and with each bit of knowledge, we need to go back to the proverbial drawing board to figure out how to get around or disable that mechanism.”

“It's like opening a little door,” he says, “and we're starting to peek at what's inside.” –Suzanne Rose