TLR9 Agonist May Reverse Resistance to Immune Checkpoint Inhibition in Melanoma

Treatment with the intratumoral Toll-like receptor 9 (TLR9) agonist CMP-001 appeared to potentially reverse resistance to immune checkpoint inhibition in patients with metastatic melanoma, inducing responses to pembrolizumab in some patients.

“There are many patients that either initially respond to checkpoint inhibition and then progress, or never respond to this therapy to begin with,” said Mohammed Milhem, MBBS, of the University of Iowa in Iowa City, according to a press release. “Finding safe and effective therapies for these patients is critical.”

Milhem presented results of a phase Ib clinical trial of the TLR9 agonist CMP-001 along with pembrolizumab at the American Association for Cancer Research Annual Meeting, held April 14–18 in Chicago (Abstract CT144). Earlier work has shown that an increase in interferon gene expression is correlated with responses to programmed death 1 (PD-1) inhibition, and the strongest known inducer of interferon production is the TLR9 pathway. “So we thought that adding a TLR9 activator to anti–PD-1 therapy would elicit a response in patients who stopped or never responded to PD-1 inhibition,” Milhem said.

The study included 44 patients in a dose-escalation phase, and 41 in a dose-expansion phase; all had advanced melanoma and had either not responded to anti–PD-1 therapy or had progressed on the treatment. CMP-001 was delivered via direct intratumoral injection, in combination with pembrolizumab therapy. There was one dose-limiting toxicity during the escalation phase, but no maximum tolerated dose was identified.

The objective response rate to the therapy was 22%, with a slightly higher response rate (23% vs 15%) among those on a weekly dosing schedule than those on an every-3-weeks schedule. Of the 15 patients who responded, 11 remain on the study, and 3 maintained a response for more than 1 year. The median duration of response has not yet been reached.

There was an abscopal effect of the treatment as well, with non-injected metastatic sites showing a reduction in volume in cutaneous, nodal, hepatic, and splenic metastases.

“Based on these preliminary findings, the combination of CMP-001 and pembrolizumab appears to have a manageable safety profile and meaningful clinical activity,” Milhem said. “Additional larger studies in this patient population will need to be conducted to further evaluate the clinical benefit, but if the current results are confirmed, it appears that this combination could offer a new treatment option for patients with advanced melanoma who are not responsive to pembrolizumab.”