Person:

Fecci, Peter

We have recently described a new murine model of glioblastoma, generated by the implantation of syngeneic glioblastoma stem cells into immunocompetent mice, that recapitulates the salient histopathological and immunological features of the human disease. We employed this model to demonstrate the multifaceted activity of an oncolytic herpes simplex virus genetically modified to express interleukin-12, G47∆-IL12.

The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition.

Warfarin-associated intracranial hemorrhage is associated with a high mortality rate. Ongoing coagulopathy increases the likelihood of hematoma expansion and can result in catastrophic hemorrhage if surgery is performed without reversal. The current standard of care for emergency reversal of warfarin is with fresh frozen plasma (FFP). In April 2013, the USA Food and Drug Administration approved a new reversal agent, 4-factor prothrombin complex concentrate (PCC), which has the potential to more rapidly correct coagulopathy. We sought to to determine the feasibility and outcomes of using PCC for neurosurgical patients. A prospective, observational study of all patients undergoing coagulopathy reversal for intracranial hemorrhage from April 2013 to December 2013 at a single, tertiary care center was undertaken. Thirty three patients underwent emergent reversal of coagulopathy using either FFP or PCC at the discretion of the treating physicians. Intracranial hemorrhage included subdural hematoma, intraparenchymal hematoma, and subarachnoid hemorrhage. FFP was used in 28 patients and PCC was used in five patients. International normalized ratio at presentation was similar between groups (FFP 2.9, PCC 3.1, p = 0.89). The time to reversal was significantly shorter in the PCC group (FFP 256 minutes, PCC 65 minutes, p < 0.05). When operations were performed, the time delay to perform operations was also significantly shorter in the PCC group (FFP 307 minutes, PCC 159 minutes, p < 0.05). In this preliminary experience, PCC appears to provide a rapid reversal of coagulopathy. Normalization of coagulation parameters may prevent further intracranial hematoma expansion and facilitate rapid surgical evacuation, thereby improving neurological outcomes.