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R.A. Brekken
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ORAL 41 - Immune Biology, Microenvironment and Novel Targets (ID 159)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.K. Padda, R. Nemenoff
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F1+F2
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ORAL41.05 - Targeting Phosphatidylserine-Mediated Immune Suppression Enhances the Efficacy of Immune Checkpoint Blockade in Pre-Clinical Tumor Models (ID 1011)
19:13 - 19:24 | Author(s): R.A. Brekken
- Abstract
- Presentation
Background:
Despite substantial progress, only a subset of cancer patients benefit from blockade of the PD-1 immune checkpoint. Multifocal immune suppression in the tumor microenvironment is the underlying cause for the limited efficacy of immune checkpoint blockade. Persistent immune suppression prevents the development of a robust T cell response to tumor specific antigens that is required for effective downstream immune checkpoint blockade. An underappreciated but significant contributor to immune suppression in tumors is the expression of the membrane phospholipid phosphatidylserine (PS) on the surface of tumor cells and tumor-derived microvesicles. PS is recognized by receptors on immune cells where it triggers the secretion of immune suppressive cytokines, prevents the differentiation of myeloid-derived suppressor cells (MDSCs) and inhibits dendritic cell (DC) maturation; events that prevent a productive anti-tumor T cell response. Bavituximab, a chimeric monoclonal antibody that targets PS and inhibits PS-mediated immunosuppressive signaling, drives immune activation by reducing the levels of MDSCs, by polarizing tumor-associated macrophages towards an M1 phenotype and by promoting the maturation of dendritic cells (DCs).
Methods:
The efficacy of bavituximab, anti-PD-1 and combination therapy was evaluated in multiple syngeneic, pre-clinical tumor models. Treatment efficacy was determined by inhibition of tumor growth and by immunophenotyping of spleen and tumor infiltrating leukocytes.
Results:
The combination of antibody-mediated PS and PD-1 blockade was significantly more effective in reducing tumor burden and promoting immune activation than single agent therapy. Combination therapy increased tumor infiltration of effector T-cells (Teff), increased the Teff:T regulatory cell ratio in the tumor and enhanced Teff function as determined by IFN-γ, TNFα and granzyme B levels associated with Teff cells in the spleen and tumor. Furthermore combined blockade of PS and PD-1 signaling reduced the level of immune suppressive cells (e.g., MDSCs, M2 macrophages, and Treg) in the tumor microenvironment.
Conclusion:
These results raise the possibility that PS blockade with bavituximab can enhance the efficacy of anti-PD-1 therapy even in patients with tumors that are unresponsive to single agent immune checkpoint therapy.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-098 - Acquired Resistance to Anti-VEGF Therapy in Non-Small Cell Lung Cancer Is Not Associated with Angiogenic Compensation (ID 2808)
09:30 - 09:30 | Author(s): R.A. Brekken
- Abstract
Background:
The vascular system provides nutrients and oxygen to cells and tissues via the circulation of blood. Tissues require an efficient vascular network to maintain homeostasis. Angiogenesis, the process of expansion and remodeling of the vascular network, is driven by the expression and secretion of angiogenic growth factors that stimulate endothelial cell migration, proliferation and survival. Induction of angiogenesis is an early event in the progression of tumors, including non-small cell lung cancer (NSCLC). Vascular endothelial growth factor-A (VEGF) is a principal angiogenic growth factor in NSCLC and as a result is an attractive therapeutic target. Despite promising preclinical results, therapies targeting VEGF have shown only modest improvements in progression free survival and overall survival in NSCLC patients. Many NSCLC patients that initially respond to anti-VEGF therapy develop resistance with continued use. We sought to determine factors associated with acquired resistance to anti-VEGF monoclonal antibodies (mAbs). r84 is a fully human anti-VEGF mAb that inhibits human and mouse VEGF binding to VEGF receptor 2 (VEGFR2) but not VEGFR1 and is currently in Phase I clinical trials. Bevacizumab is a humanized mAb specific for human VEGF that blocks VEGF from binding VEGFR1 and VEGFR2 and is currently approved for treatment of NSCLC.
Methods:
Acquired resistance to anti-VEGF therapy was driven in NSCLC cell lines (H1975, H1993, and H2073) by prolonged in vivo therapy with r84 or bevacizumab. Over 20 cell lines (e.g., H1975-81) were generated by ex vivo culture from tumors that displayed acquired resistance to therapy. In addition, tumor cell lines were generated from tumor-bearing mice treated with saline (e.g. H1975-713). A subset of control and resistant cell lines were implanted in vivo and evaluated for response to anti-VEGF therapy. Tumor microvessel density was determined by immunohistochemistry.
Results:
Two of five acquired resistance cell lines were verified as resistant upon reimplantation and treatment with r84 and bevacizumab demonstrating that the changes induced by prolonged anti-VEGF therapy in these cell lines are heritable. Conversely, tumor xenografts from saline control tumors remained sensitive to anti-VEGF therapy. Anti-VEGF therapy with r84 or bevacizumab reduced microvessel density in each tumor regardless of whether therapy reduced tumor growth or not.
Conclusion:
Anti-VEGF therapy significantly reduces angiogenesis even in tumors that show resistance to therapy, suggesting that compensation by other angiogenic growth factors is not a significant contributor to tumor response to anti-VEGF therapy. Further, prolonged treatment with anti-VEGF can induce heritable changes in NSCLC cells that confer resistance to anti-VEGF therapy.
