Varlilumab is a fully human monoclonal antibody (mAb) that targets CD27, a critical molecule in the activation pathway of lymphocytes. Like CD40, CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses, and may result in less toxicities due to its restricted expression and regulation. Varlilumab is an agonist anti-CD27 mAb that has been shown to activate human T cells in the context of T cell receptor stimulation. In pre-clinical models, varlilumab has been shown to mediate anti-tumor effects and may be particularly effective in combination with other immunotherapies. In addition to the immune enhancing properties of varlilumab, the mAb may also provide direct therapeutic effects against tumors with CD27 expression. Human B and T cell lymphomas often express CD27 at high levels and varlilumab has shown potent anti-tumor activity against these types of tumors in preclinical models. Therefore, in patients with lymphomas/leukemia that express CD27, varlilumab may function through two independent mechanisms:
T cells are typically stimulated to divide and mediate anti-tumor effects through a 2 signal mechanism that involves the T cell receptor stimulation (when engaged with an antigen presenting cell) and a co-stimulatory signal. CD27 can provide a potent co-stimulatory signal when engaged by its ligand CD70. However, CD70 is generally not available (to prevent unwanted stimulation of T cells). Varlilumab can substitute for CD70 and will cause activation of T cells that are in the appropriate setting (receiving T cell receptor stimulation). This can result in a weak immune response becoming a strong response that can last for a long time.
Direct anti-tumor effect:
Some tumors (B or T cell derived malignancies) have high CD27 expression. Varlilumab can bind these tumor cells directly and activate immune cell killing through a mechanism known as antibody dependent cellular cytotoxicity (ADCC). Varlilumab binding to the tumor cells may also interfere with tumor cell growth by additional mechanisms.
Celldex presented an in vitro study at the 2013 American Association of Cancer Research Annual Meeting analyzing the activation of human T cells with varlilumab. The results confirmed the mechanisms of action of the antibody and provided additional support for continued clinical development of the candidate. Using purified T cells from healthy subjects, the results demonstrated that concomitant signaling through the T Cell Receptor for antigen is required for varlilumab drug activity. Since the vast majority of lymphocytes will not be receiving T Cell Receptor signaling, widespread activation of T cells should not be seen. Importantly, when T cells are activated through T cell receptor stimulation and varlilumab, they undergo multiple cell divisions, secrete cytokines with a dominant proinflammatory signature (IFNγ, IL-2 and TNFα), and express activation markers consistent with an activated phenotype. Gene expression microarray analysis revealed modulation of intracellular signaling, protein kinases, growth and cytokine-chemokine pathways.
Ongoing Clinical Trials
Varlilumab is completing a Phase 2 study being conducted in collaboration with Bristol-Myers Squibb and their PD-1 immune checkpoint inhibitor, Opdivo® (nivolumab). The study completed enrollment in January 2018 with cohorts in colorectal cancer (n=21), ovarian cancer (n=58), head and neck squamous cell carcinoma (n=24), renal cell carcinoma (n=14) and glioblastoma (n=22). The primary objective of the Phase 2 cohorts is objective response rate, or ORR, except glioblastoma, where the primary objective is the rate of 12-month OS. Data from the Phase 2 colorectal and ovarian cancer cohorts were presented in an oral presentation at the American Society of Clinical Oncology (ASCO) 2018 Annual Meeting. Data from the Phase 2 GBM cohort were presented at the 2018 Society for Neuro-oncology (SNO) Annual Meeting.
For more information on the varlilumab program, view recent scientific presentations and publications.