Euroinvestor Cockpit Social Media Investment Platform Wins Best New Financial Service Application in the Danish Internet Awards 2012

Synergistic benefit of anti-tumor therapy was observed when MVA-BN-HER2 immunotherapy was combined with PD-1 immune checkpoint blockade. Interestingly, PD-1 blockade stimulated a second immune checkpoint molecule, LAG-3, to be expressed on T cells. Combining MVA-BN-HER2 immunotherapy with dual PD-1 plus LAG-3 blockade resulted in comprehensive tumor regression in all mice treated with the triple combination therapy.

In contrast, anti-PD-1 monotherapy triggered significantly higher levels of LAG-3 expression than MVA-BN-HER2 therapy but T cells remained confined to the tumor periphery. Combining MVA-BN-HER2 immunotherapy with PD-1 blockade resulted in high LAG-3 expression on CD8 T cells and CD8 T cell infiltration throughout the tumor and co-localization of CD4 and LAG-3 in patches of the tumor . Increased tumor infiltration by CD4 T cells was observed in both groups treated with MVA-BN-HER2 but was only significant in the combination treatment group .

S4 Fig. LAG-3 and CD4 expression in the tumor microenvironment after MVA-BN-HER2 and anti-PD-1 therapy.

There appear to be two mechanisms for PD-L1 up-regulation in tumors—innate and adaptive resistance. Innate resistance is driven by aberrant oncogenic signaling pathways and results in tumor cells that constitutively express PD-L1 . In contrast, adaptive resistance occurs in response to IFNγ produced by tumor-infiltrating T cells provoking PD-L1 upregulation on cells in the tumor microenvironment . PD-1 axis blockade confers significant clinical benefit, especially for patients with a pre-existing T cell-inflamed tumor microenvironment characterized by CD8+ and PD-1/PD-L1+ cells .

Growth Analysis

The program will also include clinicians who will discuss their perspectives on the use of the products in the real world setting. The didactic presentations will be short to leave time for audience questions. Cockpit is a cloud and social media-based app dashboard which means that it can be accessed from any Flash-compatible device with an internet connection, and shared in social media platforms such as Facebook and Twitter. No software installation is required, which makes the process of getting started to invest both quick and easy. MC38-MUC1 cells were stimulated with varying concentrations of IFNγ for 18 hours. A) Percent of cells expressing PD-L1 and the mean fluorescence intensity by flow cytometry.

Elevated PD-L1 expression as a tumor immune evasion mechanism to suppress the activity of tumor-infiltrating, IFNγ-producing T cells was also demonstrated in humans . Recent clinical studies demonstrated a correlation between PD-L1 expression with the presence of TILs . Indeed, PD-1/PD-L1 inhibition appears to provide higher clinical benefit for those patients with PD-L1 positive tumors . Together, these correlations suggest that patients with an endogenous or pre-existing tumor-specific T cell immune response may be most likely to benefit from PD-1/PD-L1 axis blockade. However, this leaves a high unmet need for patients with PD-L1neg/low tumors.

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Consistent with this hypothesis, comprehensive and durable tumor regression was observed in 100% of mice treated with this triple combination therapy . Strikingly, tumors were observed to grow in size following initiation of the combination therapy, yet regressed completely upon the second administration two weeks after the first dose . The complete efficacy of triple combination therapy was greater than anti-PD-1 and anti-LAG-3 immune checkpoint blockade or MVA-BN-HER2 immunotherapy plus anti-PD-1 or MVA-BN-HER2 immunotherapy plus LAG-3 blockade . Mice that rejected their tumor after any treatment remained tumor-free more than 5 months after the initial tumor challenge .

In Vivo Studies

We therefore postulated that patients may benefit from combining activation of tumor-specific effector T cells through poxvirus-based active immunotherapy with dual PD-1 and LAG-3 checkpoint inhibition. Naturally occurring or immunotherapy-induced immune responses are kept in-check by the immune system through kryptovaluta engagement of immune checkpoint molecules. Effector T cells simultaneously express multiple inhibitory immune checkpoint molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death receptor-1 (PD-1), lymphocyte activation gene-3 (LAG-3), and others to control the immune response .

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