Abstract
MHC expression may affect response to immune checkpoint inhibitors in patients with advanced melanoma. In a recent retrospective analysis, patients with low MHC class I expression responded to a PD-1 inhibitor, but were less likely to respond to a CTLA4 inhibitor than patients with higher MHC class I expression.
The presence of MHC proteins may affect response to immune checkpoint inhibitors in patients with advanced melanoma: In a recent retrospective study, patients with low MHC class I expression responded to a PD-1 inhibitor but were less likely to respond to a CTLA4 inhibitor (Sci Transl Med 2018; 10:eaar3342). Additionally, patientswho expressed MHC class II had better responses to a PD-1 inhibitor.
“T-cell recognition of cancer-specific mutant peptides, in the context of MHC, is generally what's thought to be essential for antitumor immunity, and this activity is enhanced when you treat patients with agents that target immune checkpoints,” says Scott Rodig, MD, PhD, of Dana-Farber/Harvard Cancer Center in Boston, MA, the study's lead author. However, “it all hinges upon the idea that the cancer cell is able to actually present these mutant proteins to the immune system, and for the immune system to recognize them.”
In a previous study of patients with classic Hodgkin lymphoma, Rodig and colleagues discovered a paradox: The disease is highly responsive to a PD-1 inhibitor, but most tumor cells do not express MHC class I (Cancer Immunol Res 2016;4:910–6). They concluded that an alternate mechanism must be triggering a response.
“Once we found this in Hodgkin lymphoma, it was sort of an open question of, ‘Could downregulation of MHC I be a mechanism at play in other tumor types?’ ” Rodig says.
To answer this question, the researchers conducted a retrospective study of 138 patients with advanced melanoma in the phase II CheckMate 064 trial who had received either 13 weeks of the CTLA4 inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) followed by 13 weeks of the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb), or vice versa. They performed immunohistochemical staining on biopsy samples taken before treatment and looked at MHC class I and class II expression. They then correlated the results with transcriptional and genomic profiles and clinical outcomes.
Patients responded to 13 weeks of nivolumab regardless of whether they expressed MHC class I, suggesting that “if MHC class I antigen presentation is compromised, there are alternativemechanisms for activating an antitumor response,” Rodig says. A possible mechanism is MHC class II: Patientsfirst treated with nivolumab for 13 weeks who lacked MHC class I expression but expressed MHC class II in more than 1% of tumor cells had better responses and improved overall survival (OS) than patients with low MHC class II expression.
Patients first treated with ipilimumab for 13 weeks who had MHC class I expression in 30% or fewer cells were more likely to have progressive disease after 13 weeks than patients with higher MHC class I expression, and patients with expression in 50% or fewer cells had worse OS than patients with higher MHC class I expression, an indication that “antitumor immunity that is unleashed by CTLA4 blockadeis exquisitely sensitive to retained expression of MHC class I by melanoma cells,” Rodig says.
For Douglas Johnson, MD, of Vanderbilt-Ingram Cancer Center in Nashville, TN, who was not involved in the research, it confirms a positivecorrelation between MHC class II expression and response to a PD-1 inhibitor established in previous research (Nat Commun 2016;7:10582). “MHC class II has now been validated in a few different studies as a potential biomarker for PD-1 [inhibitor response], and I think that it does look promising, although it still has a long way to go,” he says.
Adil Daud, MD, of the University of California, San Francisco, who was also not connected to the research, is intrigued by the link between MHC class I expression and response to ipilimumab because it may indicate that the drug works via a different mechanism than has been thought.
“The mystery of how ipilimumab works, in my mind, has just grown over the years, because people have not been able to nail down a good biomarker,” he says. “What this paper is suggesting is that maybe we weren't looking in the right place.” –Catherine Caruso
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