New immunotherapy combination shows promise for melanoma treatment

A clinical trial by University of Iowa oncologist Mohammed Milhem, MBBS, shows promising findings on treatment of metastatic melanoma. Milhem presented the early study results April 17 at the 2018 American Association for Cancer Research (AACR) meeting in Chicago.

The treatment used in the phase 1b clinical trial combined a powerful immune system activator with the immunotherapy agent pembrolizumab (Keytruda). The study shows the combination was well tolerated in patients and suggests it could be effective against advanced melanoma that has either not responded to or has progressed during therapy with the pembrolizumab alone.

Checkpoint inhibitors, like pembrolizumab, are now the standard of care for metastatic melanoma, but more than 50 percent of these patients develop resistance, says Milhem, who is director of the melanoma program and deputy director for clinical research and clinical services at Holden Comprehensive Cancer Center at the UI.

“Finding safe and effective therapies for these patients is critical,” he adds.

Based on early UI cancer research

The new study is being conducted with Checkmate Pharmaceuticals. This UI-industry partnership and the fundamental science behind the clinical trial have been more than two decades in the making.

In 1994, Art Krieg, now CEO of Checkmate Pharmaceuticals, was a UI researcher when he discovered that CpG oligonucleotides are powerful activators of the innate immune system. The thinking at the time was that simply boosting the immune system would be sufficient to fight cancer, but results were disappointing. The tipping point didn’t arrive until almost 20 years later with the development of checkpoint inhibitors, immunotherapy drugs that essentially take the brakes off the immune system and allow T-cells to recognize and attack cancer cells.

“The checkpoint inhibitors bring the T-cells to the tumor, but the T-cells are still inhibited from attacking because the tumor cells are able to make the T-cells tolerate them,” explains Milhem. “CpG breaks the tolerance between the T-cell and the tumor, allowing the system to go forward. Pembrolizumab removes the brakes, the CpG molecule removes the tolerance, then you get good response.”

The new trial tested a combination of the Checkmate drug CMP-001—a CpG-A oligonucleotide that activates the innate immune system via Toll-like receptor 9 (TLR9)—with pembrolizumab (Keytruda) in patients with advanced melanoma who had either not responded to or had progressed during prior anti-PD-1 therapy. The CMP-001 is injected into some of the patients’ tumors.

Current study results

As of late March 2018, 85 patients have been treated in the trial; 44 patients were enrolled in the dose escalation phase, while 41 patients have been enrolled in the ongoing dose expansion phase.

So far, across both the dose escalation and expansion cohorts, 15 patients have responded. Among these 15, 11 remain on study and three have maintained their response beyond one year.

Notably, Milhem and colleagues saw reductions in size for tumors that were directly injected and also in non-injected tumors (a so-called abscopal effect), which Milhem says is a hallmark of successful intratumoral immunotherapy treatment.

Future studies likely

“Based on these preliminary findings, the combination of CMP-001 and pembrolizumab appears to have a manageable safety profile and meaningful clinical activity,” Milhem says. “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.”

This study is sponsored and managed by Checkmate Pharmaceuticals. Milhem declares no conflict of interest.