Emerging Immunotherapy Target in Spotlight at Wistar

Dmitry I. Gabrilovich, MD, PhD

Amid growing evidence of their importance in the immune system, myeloid-derived suppressor cells (MDSCs) are gaining traction as a target for anticancer therapies, according to Dmitry I. Gabrilovich, MD, PhD, a leading expert in the field.

More than 200 scientists from research centers throughout the world gathered June 16-19 at the Wistar Institute in Philadelphia to share their insights into the mechanisms and activity of MDSCs in the immune system. Gabrilovich, a professor and leader of the Translational Tumor Immunology Program at Wistar, organized the 4-day conference, entitled “Regulatory Myeloid Suppressor Cells: From Basic Discovery to Therapeutic Application.”

Gabrilovich said the meeting was one of the first specialized conferences to focus on MDSCs, and the level of interest is indicative of the potential importance of targeting the cells therapeutically. He said approximately 20 companies had participated in the conference through sponsorships or presentations.

MDSCs are part of the network of cells that regulates the immune response to cancer, said Gabrilovich. “It’s basically a very important negative checkpoint inhibitor,” he said in an interview with OncLive. “These cells expand in patients with cancer, usually in the more advanced stages. They block immune response either spontaneously or induced by therapy.”

Gabrilovich, one of the first researchers to delineate the potential importance of MDSCs, described the cells as distinct from mature myeloid cells such as macrophages, dendritic cells, and neutrophils in a recent article in The Journal of Clinical Investigation.¹ MDSCs can be divided into 2 major subsets: myeloid progenitor and immature mononuclear cells similar to monocytes, and immature polymorphonuclear cells similar to neutrophils.¹

Although cells with similar characteristics had been observed since the late 1970s, the potential importance of MDSCs started to be more specifically described in the late 1990s, said Gabrilovich. He helped coin the term MDSC in 2007.²

He said MDSCs have become more relevant in research as the growing number of immunotherapy options in oncology rely on the functioning of the patient’s immune system to generate a response. In mouse studies, targeting MDSCs in combination with immunotherapeutic interventions is generating strong antitumor activity, Gabrilovich said.

Gabrilovich said researchers are examining 2 roles for MDSCs, which can be identified in peripheral blood, in clinical practice. The first is as a prognostic indicator of the outcome of cancer in early stages, as reports link accumulation of the cells in patients’ blood with negative results. He said many immunotherapy trials have integrated analysis of participants’ MDSC levels into the studies.

The second focus is therapeutic, as researchers seek to target the cells directly or indirectly to affect the tumor microenvironment. “If you target the cells effectively, you change the nature, the architecture of the tumor microenvironment,” Gabrilovich said.

Combination Studies Underway

MDSCs can be attacked in a variety of ways. Wesolowski et al described 4 major strategies that are under investigation for inhibiting MDSCs: (1) deactivating MDSCs, with potential options including PDE-5 and colony stimulating factor receptor 1 inhibitors; (2) differentiating MDSCs into mature cells through the use of all-trans-retinoic acid or other agents; (3) blocking development of MDSCs with bisphosphonates or inhibitors of the JAK/STAT or VEGF pathways; and (4) depleting MDSCs with cytotoxic agents such as gemcitabine or cisplatin.³One budding area of research consists of combining agents that target MDSC activity with checkpoint immunotherapies.

The novel agent omaveloxolone (RTA 408) is being evaluated in the phase Ib/II REVEAL trial in combination with either ipilimumab (Yervoy) or nivolumab (Opdivo) in patients with advanced unresectable or metastatic melanoma.⁴

In animal studies, omaveloxolone has been shown to reduce tumor nitrotyrosine burden, a byproduct of reactive molecules that nurture the immunosuppressive effects of MDSCs, and to enhance T-cell anticancer activity.⁴

In the REVEAL trial, participants receive omaveloxolone tablets (2.5 mg/capsule) once daily for 1 week prior to initiation of ipilimumab or nivolumab, followed by combined therapy with either of the checkpoint inhibitors, and then maintenance therapy with omaveloxolone until progression.⁴ The trial, which aims to enroll 84 patients, is being conducted by Reata Pharmaceuticals, a Texas-based company, in collaboration with AbbVie.

Another example of MDSC-related developmental efforts is bavituximab, a monoclonal antibody that blocks immunosuppressive signaling mediated by phosphatidylserine (PS), resulting in a reduction in the levels of MDSCs in the tumor microenvironment.

Efforts to combine bavituximab with docetaxel as a treatment for patients with stage IIIb/IV nonsquamous non—small cell lung cancer (NSCLC) faltered earlier this year when the phase III SUNRISE trial was halted after a futility analysis, according to Peregrine Pharmaceuticals, the company developing the drug.

Development efforts, however, are continuing on several fronts. A phase II study is currently being designed to assess the PD-L1 inhibitor durvalumab with or without bavituximab for patients with previously treated metastatic NSCLC. This trial was initiated in February 2016 and has not yet started to recruit patients (NCT02673814).

Additionally, a phase II study of neoadjuvant bavituximab in combination with paclitaxel in patients with early-stage triple-negative breast cancer is planned (NCT02685306).

Gabrilovich is involved in several clinical studies focused on MDSC strategies, although he did not want to discuss the details of those efforts. Wistar is a National Cancer Institute—designated cancer center devoted to basic research that helps translate discoveries through partnerships with academic medical centers and biopharmaceutical companies.

References

1. Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015;125(9):3356-3364.
2. Gabrilovich DI, Bronte V, Chen SH, et al. The terminology issue for myeloid-derived suppressor cells [letter]. Cancer Res. 2007;67(1):425.
3. Wesolowski R, Markowitz J, Carson WE. Myeloid derived suppressor cells—a new therapeutic target in the treatment of cancer. J Immunother Cancer. 2013;1:10. doi:10.1186/2051-1426-1-10. eCollection 2013.
4. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02259231.