Abstract
Varlilumab activates the CD27 pathway in T cells to promote antitumor activity in solid tumors.
Major finding: Varlilumab activates the CD27 pathway in T cells to promote antitumor activity in solid tumors.
Clinical relevance: Varlilumab was well tolerated in a phase I trial of patients with advanced solid tumors.
Impact: Varlilumab warrants further investigation in combination with other therapies in patients with cancer.
CD27 is a costimulatory T-cell receptor that, when bound by its ligand CD70 in concert with T-cell receptor (TCR) stimulation, promotes T-cell activation, proliferation, survival, and maturation of effector and memory T cells, suggesting the possibility that CD27 activation could be an immunotherapeutic approach to generate antitumor T cells. Varlilumab is a first-in-class anti-CD27 monoclonal antibody that acts as a CD27 agonist. In mouse models, varlilumab induces antitumor immunity, prompting Burris and colleagues to evaluate the safety, pharmacology, and activity of varlilumab monotherapy in an open-label phase I dose-escalation and expansion study in patients with advanced solid tumors. The dose-escalation phase included 25 patients with colorectal cancer, melanoma, ovarian cancer, prostate cancer, renal cell carcinoma (RCC), or non–small cell lung cancer. The dose-expansion cohorts included 16 patients with melanoma and 15 patients with RCC. The primary objectives were to determine the safety, maximum tolerated dose, and optimal biologic dose of varlilumab. Secondary objectives included assessment of varlilumab pharmacokinetics, pharmacodynamics, and antitumor activity. Pharmacokinetic analysis showed sustained varlilumab exposure during treatment cycles, and varlilumab treatment resulted in chemokine induction, T-cell stimulation, and regulatory T-cell depletion, consistent with on-target activation of CD27. Varlilumab was well tolerated; most treatment-related adverse events were grade 1 or 2, and only one dose-limiting toxicity occurred. The maximum tolerated dose was not reached. One patient with metastatic RCC achieved a durable partial response and 8 patients experienced stable disease. Collectively, the results of this phase I trial suggest that varlilumab activates the CD27 pathway, is well tolerated, and has antitumor activity in patients with advanced solid tumors, suggesting the possibility of combining varlilumab with other immunotherapies or traditional therapies.
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