Poxvirus-Based Active Immunotherapy with PD-1 and LAG-3 Dual Immune Checkpoint Inhibition Overcomes Compensatory Immune Regulation

Poxvirus-Based Active Immunotherapy with PD-1 and LAG-3 Dual Immune Checkpoint Inhibition Overcomes Compensatory Immune Regulation, Yielding Complete Tumor Regression in Mice PLOS ONE

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 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 .

These data support the clinical investigation of this triple therapy regimen, especially in cancer patients harboring PD-L1neg/low tumors unlikely to benefit from immune checkpoint blockade alone. Poxvirus-based active immunotherapy results in significant antitumor immunity characterized by robust CD8 T cell infiltration of the tumor . The studies in this report show that this is also accompanied by significant upregulation of PD-L1 expression in the tumor microenvironment, a known adaptive resistance mechanism that occurs in response to IFNγ produced by tumor-infiltrating T cells . When MVA-BN-HER2 immunotherapy was combined with PD-1 blockade, synergistic anti-tumor efficacy was observed, and in 45% of mice the tumors regressed completely.

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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.

Conversely, without an endogenous anti-cancer T cell immune response, as presumed in cancer patients harboring PD-L1neg/low tumors, the immune checkpoint blockade is unfocused and not expected to confer significant clinical benefit . We hypothesized that poxvirus-based immunotherapy would drive antigen-specific T cells to the tumor, concomitant with IFNγ production, thus inducing PD-L1 expression in the tumor microenvironment. Therefore, this otherwise productive immune response would be enabled into synergistic anti-tumor efficacy when combined with PD-1 axis blockade. These data corroborate evidence from preclinical studies demonstrating that tumors do not upregulate PD-L1 expression in mice lacking T cells or in IFNγ-knockout mice .

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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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 kryptovaluta 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 .

The preclinical data presented here suggest that these patients may benefit from PD-1 axis blockade if combined with poxvirus-based active immunotherapies that provoke a productive tumor-infiltrating CD8 T cell response. These data further suggest that the evolution of tumors from PD-L1neg/low to PD-L1hi may be useful as a biomarker for the emergence of productive anti-tumor T cell immunity. Antigen spread is thought to play a critical role in successful immunotherapy as the immune system adapts to target novel tumor antigens as well as restricts tumor evasion to therapy.