HAMPTON, NJ, USA I April 20, 2015 I Celldex Therapeutics, Inc. (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(R), 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.
SOURCE: Celldex Therapeutics
Post Views: 57
HAMPTON, NJ, USA I April 20, 2015 I Celldex Therapeutics, Inc. (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(R), 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.
SOURCE: Celldex Therapeutics
Post Views: 57
