Siglec-15: An Attractive Immunotherapy Target

The immuno-oncology landscape has seen a slew of molecular targets and associated therapies emerge of late, albeit with inconsistent efficacy data. A new contender, however, is Siglec-15, along with its experimental monoclonal antibody, NC318 (NextCure).

Siglec-15, an immunoglobulin-like protein that binds sialic acid, is similar in sequence to PD-L1. Its key role in dampening antitumor immunity was characterized earlier this year by Lieping Chen, MD, PhD, of Yale University in New Haven, CT (Nat Med 2019;25:656–66). The discovery has roots in Chen's extensive studies of the PD-1–PD-L1 pathway, years before nivolumab (Opdivo; Bristol-Myers Squibb) and other immune checkpoint inhibitors were developed.

“Even as we began using words like ‘cold tumors’ to describe a lack of response to these drugs,” he remarked, “I thought another interpretation could simply be that this pathway isn't used by many cancers” to escape immune surveillance. Indeed, PD-1–PD-L1 orchestrates such evasion in less than half of solid tumors, so Chen's group set out to find additional operators of immune dysfunction in the tumor microenvironment (TME).

Using a functional screening assay to pinpoint modulators of T-cell activity, the researchers landed on Siglec-15. They found that it is minimally expressed in normal tissue, but widely upregulated on tumor cells and tumor-associated myeloid cells as well as M2 macrophages, leading to profound immunosuppression in the TME. How this happens is not fully understood, but “our data support a mechanism where Siglec-15–expressing cells can interact directly with T cells and shut them down,” Chen explained.

Notably, Siglec-15 expression is mutually exclusive with that of PD-L1: Where the latter is induced by IFNγ, Siglec-15 is downregulated—and vice versa. “It's why we think this is an independent, interesting target,” Chen added. A drug that alleviates Siglec-15–driven immunosuppression could be viable in patients who, with low or no PD-L1 expression, would not benefit from current checkpoint blockade.

Buoyed by preclinical results, Chen has been developing a Siglec-15 antibody, NC318, with Beltsville, MD–based biotech NextCure, for which he is the scientific founder. Preliminary findings from a phase I study of NC318 were highlighted during the Society for Immunotherapy of Cancer 2019 Annual Meeting in National Harbor, MD. Anthony Tolcher, MD, of NEXT Oncology in San Antonio, TX, reported that among 49 patients with a variety of tumor types, including non–small cell lung cancer (NSCLC), NC318 was safe and well tolerated. The main side effects were diarrhea and asymptomatic amylase and lipase elevations. Several cases of vitiligo—“considered a marker of immune activation,” Tolcher said—were also observed.

Efficacy isn't always seen in phase I trials, but two patients with NSCLC responded to NC318—one completely, the other partially. Both had received prior chemotherapy and PD-1 blockade, to which the best response was stable disease that then progressed. Noting that they had low levels of PD-L1, Tolcher agreed that NC318 could become a valuable therapy for this subset of patients, “where there's a great unmet need” once disease progression occurs on standard treatment. Patients with several other tumor types experienced stable disease lasting at least 6 months.

Based on this early but encouraging efficacy, NC318 is undergoing phase II evaluation for NSCLC, as well as ovarian, head and neck, and triple-negative breast cancers. Chen hopes the data will hold up and pave the way for additional Siglec-15–targeted agents, potentially mirroring anti–PD-1 therapy's success.

“Some recent prospective drugs have been more about boosting systemic immune responses to higher levels, which could result in unwanted issues,” he pointed out. Rather, “we believe normalizing defective immunity in the TME is something that can be done much more precisely, with minimal damage on the side.” –Alissa Poh

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