Celldex's Varlilumab Demonstrates Synergistic Anti-Tumor Activity with PD-1 Signaling Blockade in Preclinical Studies
April 20 2015 - 8:01AM
Celldex Therapeutics, Inc. (Nasdaq:CLDX) announced today
preclinical results that further support varlilumab's expansion
into combination studies with PD-1 inhibitors. The data were
presented in a poster session entitled "Synergistic anti-tumor
activity of PD-1 signaling blockade and CD27 costimulation
correlates with enhanced ratio of effector to regulatory T cells at
the tumor site" at the 2015 American Association for Cancer
Research Annual Meeting.
Varlilumab is a fully human immunoglobulin (Ig)G1 agonist
antibody that binds to and activates CD27, a critical T-cell
co-stimulatory molecule in the immune-activation cascade. Specific
and controlled activation of CD27 in the presence of T-cell
receptor (TCR) signaling by varlilumab results in enhanced immune
responses with a favorable safety profile. Varlilumab is in
clinical development for a range of cancers in combination with
other therapies that target potentially synergistic points of
immune-regulation, including with Opdivo®, BMS's PD-1 blocking
antibody and with MPDL3280A, Roche's anti-PDL1 investigational
cancer immunotherapy.
"These latest studies demonstrate that the combination of
varlilumab and anti-PD-L1 induces a potent immune-mediated effect
that results in important changes in the tumor microenvironment,"
said Tibor Keler, PhD, Co-founder, Executive Vice President and
Chief Scientific Officer of Celldex Therapeutics. "Most notably, we
observed that the combination strategy improved the ratio of
effector T cells to regulatory T cells, which was accompanied by a
reduction in the expression of PD-1 on both effector and regulatory
T cells. Overall these studies, along with our clinical data where
varlilumab has demonstrated anti-tumor activity with minimal
toxicity in advanced, refractory disease, provide strong rationale
for us to broadly explore varlilumab in combination with a number
of complementary investigational and approved oncology drugs,
including agents that work through the PD-1 signaling blockade."
Key findings: The combination of varlilumab and
anti-PD-L1 resulted in a significant improvement in survival over
monotherapy in multiple preclinical tumor models, including a CT-26
colon model, an E.G7 thymoma model and a BCL1 disseminated lymphoma
model. The properties of the BCL1 lymphoma model allowed for
further analysis into the mechanism of synergy between varlilumab
and anti-PD-L1. Importantly, mice cured by the combination therapy
were shown to have developed protective immunity against the BCL1
tumor, demonstrating that a long lasting and potent memory response
was generated during treatment. Additional key observations were
made by analyzing the spleens (the primary site of tumor growth)
following treatment. The major changes associated with the
combination therapy included:
- A greater reduction in tumor cells (as measured by % decrease
in CD19+ cells)
- Increased numbers of functional CD4+ and CD8+ T cells (as
measured by IFNγ production)
- An increase in the ratio of CD8+ T cells (effector T cells) to
regulatory T cells or Tregs
- A notable increase in myeloid cells, particularly
neutrophils
These changes at the site of tumor growth, particularly the
balance between effector T cells and regulatory T cells, are
consistent with an immune-mediated effect resulting in the
destruction of tumor cells. The increase in myeloid cells merits
further investigation into their role in the combination therapy
effect. Other changes including increases in natural killer cells
and decreased PD-1 expression on T cells were noted, but these were
similar in magnitude to the monotherapy treatments.
About Varlilumab
Varlilumab is a fully human monoclonal antibody that targets
CD27, a critical molecule in the activation pathway of lymphocytes.
CD27 can be effectively manipulated with activating antibodies to
induce potent anti-tumor responses and may result in fewer
toxicities due to its restricted expression and regulation.
Varlilumab is a potent anti-CD27 agonist that induces activation
and proliferation of human T cells when combined with T cell
receptor stimulation. In lymphoid malignancies that express CD27 at
high levels, varlilumab may have an additional mechanism of action
through a direct anti-tumor effect. Varlilumab has completed a
Phase 1 dose-escalation study, demonstrating potent immunologic
activity consistent with its mechanism of action and sustained
anti-tumor activity in patients with advanced, refractory disease.
No maximum tolerated dose was reached and minimal toxicities were
observed. Celldex has initiated a broad development program for
varlilumab to explore its role as an immune activator in
combination with a number of complementary investigational and
approved oncology drugs. Varlilumab is currently being studied in
three Phase 1/2 combination studies and several additional
combination studies will be initiated in 2015.
About Celldex Therapeutics, Inc. Celldex is
developing targeted therapeutics to address devastating diseases
for which available treatments are inadequate. Our pipeline is
built from a proprietary portfolio of antibodies and
immunomodulators used alone and in strategic combinations to create
novel, disease-specific therapies that induce, enhance or suppress
the body's immune response. Visit www.celldex.com. Celldex
Forward Looking Statement This release contains
"forward-looking statements" made pursuant to the safe harbor
provisions of the Private Securities Litigation Reform Act of 1995,
including those related to the Company's strategic focus and the
future development and commercialization (by Celldex and others) of
RINTEGA® ("rindopepimut"; "rindo"; CDX-110), glembatumumab vedotin
("glemba"; CDX-011), varlilumab ("varli"; CDX-1127), CDX-1401,
CDX-301 and other products and our goals for 2015. Forward-looking
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Although management believes that the expectations reflected in
such statements are reasonable, they give no assurance that such
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to a number of risks and uncertainties, including, but not limited
to, our ability to successfully complete research and further
development and commercialization of RINTEGA, glembatumumab vedotin
and other drug candidates; our ability to obtain additional capital
to meet our long-term liquidity needs on acceptable terms, or at
all, including the additional capital which will be necessary to
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CONTACT: Celldex Company Contacts:
Investors:
Sarah Cavanaugh
Vice President of Investor Relations &
Corp Communications
Celldex Therapeutics, Inc.
(781) 433-3161
scavanaugh@celldex.com
or
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