On November 6, 2015 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported new preclinical data on varlilumab, a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade (Press release, Celldex Therapeutics, NOV 6, 2015, View Source [SID:1234508066]). Results suggest that cancers may respond to CD27 immune modulation by independent mechanisms, such as immune co-stimulation and regulatory T cell (Treg) depletion. Varlilumab has the unique ability to act through both of these mechanisms. The new data were presented in a poster entitled "The mechanism of anti-tumor immunity induced by varlilumab, a CD27 agonist mAb, is model dependent" at the Society for the Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting.
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"Our data show that CD27 modulation through varlilumab results in immune activation and suppression of Treg activity, either of which can be independently responsible for a therapeutic effect, depending on the cancer model," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "Because individual human cancers are also likely to have different sensitivities to these anti-tumor activities, varlilumab’s ability to act through both mechanisms provides the broadest potential for therapeutic benefit. Our collection of preclinical and clinical results to date support Celldex’s broad clinical development program across tumor types and in combinations with other anti-tumor agents."
To better understand each mechanism separately, scientists engineered varlilumab to possess either strong co-stimulatory activity (varli-mG1) or strong Treg suppression activity (varli-mG2a) and analyzed their efficacy in several preclinical tumor models. The data indicated that potent co-stimulation activity was required for therapeutic activity in a BCL1 lymphoma model, whereas control of Tregs was required for activity in several other models, such as E.G7 thymoma, CT26 colorectal and colon 26. Importantly, varlilumab has a combination of immune co-stimulation and Treg depleting activity and demonstrated potent anti-tumor activity in all the models.
The immune stimulating and Treg depleting effects of varlilumab were also observed in Celldex’s Phase 1, single-agent clinical trial of varlilumab in patients with refractory, advanced cancers. Specifically, varlilumab administration was associated with a rapid and transient induction of pro-inflammatory cytokines, activation of T cells as assessed by increased HLA-DR expression and a significant decrease in circulating Tregs. The study also demonstrated promising clinical activity. Two patients experienced durable objective responses including a complete response in Hodgkin lymphoma (18.9+ months) and a partial response in renal cell carcinoma (13.6+ months). Thirteen patients experienced stable disease (3-36.2+ months). Varlilumab was very well tolerated and demonstrated minimal toxicity, even in elderly patients. There was no indication of immune-mediated adverse events often seen with other immunotherapies.
Varlilumab is currently being studied in multiple ongoing Phase 1/2 clinical trials with several anti-tumor agents, including nivolumab (Opdivo), ipilimumab (Yervoy) and sunitinib (Sutent) in advanced-stage cancers. Efforts are underway for additional Phase 2 studies with varlilumab, including a combination with atezolizumab (Roche’s anti-PDL1 antibody), and the Company will provide updates on these studies as they are initiated.