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 in Phase 2 development for the treatment of several cancers, and the study is being conducted in collaboration with Bristol-Myers Squibb and their PD-1 immune checkpoint inhibitor, Opdivo® (nivolumab). The ongoing Phase 2 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 colorectal and ovarian cancer cohorts will be presented in an oral presentation at the American Society of Clinical Oncology (ASCO) 2018 Annual Meeting, and data from remaining cohorts will be presented at future medical meetings in 2018.
Data from the Phase 1 dose escalation portion of the study were presented in an oral presentation at the ASCO Annual Meeting in June 2017. The majority of the 36 patients enrolled had PD-L1 negative tumor at baseline and presented with stage IV, heavily-pretreated disease. 80% of patients enrolled presented with refractory or recurrent colorectal (n=21) or ovarian cancer (n=8), a population expected to have minimal response to checkpoint blockade. The primary objective of the Phase 1 portion of the study was to evaluate the safety and tolerability of the combination. The combination was well tolerated at all varlilumab dose levels tested without any evidence of increased autoimmunity or inappropriate immune activation.
Marked changes in the tumor microenvironment including increased infiltrating CD8+ T cells and increased PD-L1 expression, which have been shown to correlate with a greater magnitude of treatment effect from checkpoint inhibitors in other clinical studies, were observed. Additional evidence of immune activity, such as increase in inflammatory chemokines and decrease in T regulatory cells, was also noted. Notable disease control was also observed (stable disease or better for at least 3 months), considering the stage IV patient population contained mostly colorectal and ovarian cases (80%): 0.1 mg/kg varlilumab + 240 mg Opdivo: 1/5 (20%), 1 mg/kg varlilumab + 240 mg Opdivo: 5/15 (33%) and 10 mg/kg varlilumab + 240 mg Opdivo: 6/15 (40%).
Three partial responses (PR) were observed. A patient with PD-L1 negative, MMR proficient colorectal cancer, typically unlikely to respond to checkpoint blockade monotherapy, achieved a confirmed PR (95% decrease in target lesions) and, following completion of combination treatment, continues to receive treatment with Opdivo monotherapy at 22+ months. A patient with low PDL1 (5% expression) squamous cell head and neck cancer achieved a confirmed PR (59% shrinkage) and experienced progression free survival of 6.7 months. A patient with PD-L1 negative ovarian cancer experienced a single timepoint PR (49% shrinkage) but discontinued treatment to a dose-limiting toxicity (immune hepatitis, an event known to be associated with checkpoint inhibition therapy). A subgroup analysis was conducted in patients with ovarian cancer based on an observed increase of PD-L1 and tumor infiltrating lymphocytes in this patient population. In patients with paired baseline and on-treatment biopsies (n=13), only 15% were PD-L1 positive (> 1% tumor cells) at baseline compared to 77% during treatment (p=0.015). Patients with increased tumor PD-L1 expression and tumor CD8 T cells correlated with better clinical outcome with treatment (stable disease or better).
For more information on the varlilumab program, view recent scientific presentations and publications.