Novel immune checkpoint holds ‘great promise’ as melanoma treatment target

MILAN – DC-HIL is a novel immune checkpoint with “great promise” as a treatment target for melanoma and other cancers, Ponciano D. Cruz Jr., MD, said at the World Congress of Dermatology.

^{Andrew D. Bowser/MDedge News}

Dr. Ponciano Cruz

Dr. Cruz, who along with colleagues discovered the immune checkpoint, have generated an anti–DC-HIL monoclonal antibody, which he said dramatically reduces melanoma growth and metastasis in animal models.

That antibody has also been shown to block the T-cell suppressor function of myeloid-derived suppressor cells (MDSCs), according to Dr. Cruz, who is with the department of dermatology at the University of Texas Southwestern Medical Center, Dallas.

“To date, we haven’t subjected our antibodies to clinical trials, but that will happen soon,” he said in an oral presentation at the meeting.

Also referred to as GPNMB, DC-HIL exists as a cell-bound receptor, and as a soluble factor secreted into circulation, according to Dr. Cruz.

In healthy subjects, DC-HIL is expressed in low levels by certain immune cells but is highly expressed by MDSCs in patients with melanoma, as well as other cancers including breast, colorectal, kidney, lung, and prostate cancers, he said. Those MDSCs expand exponentially as malignancies progress, he noted.

Soluble DC-HIL can be detected in the blood of many patients, and at increasing levels with metastasis, he added. DC-HIL–positive MDSC, and soluble DC-HIL, are blood markers that “may prognosticate the course and response to treatment of these cancers,” he said.

The researchers have demonstrated that DC-HIL inhibits T-cell activation by binding to its ligand, syndecan-4, on effector T cells, Dr. Cruz told attendees. “Thus, DC-HIL/syndecan-4 is a coinhibitory pathway akin to immune checkpoints CTLA4 [cytotoxic T-lymphocyte antigen 4] and PD-1 [programmed death-1],” he said.

In DC-HIL knockout mice, melanoma growth is suppressed in comparison to melanoma growth in wild-type mice, Dr. Cruz and colleagues have found in previous experiments. They subsequently found that their anti–DC-HIL monoclonal antibody reduced melanoma growth and metastasis in mice.

The antibody reversed the T-cell suppressor effect of MDSC in patients with metastatic melanoma and other cancers, he said.

Dr. Cruz has reported a disclosure (patents, royalties, other intellectual property) related to the use of anti–DC-HIL antibodies for cancer diagnosis, prognosis, and therapy.