Immu-37. Vemurafenib Enhances the Cytotoxicity of Ny-eso-1 Tcr Engineered T-cells for Braf Mutant Brain Tumors
Year: 2018
Type: conference-abstract
Abstract: Missense BRAF mutations are found in a significant portion of pediatric brain tumors, leading to constitutive MAPK pathway activation. By combining immunotherapy with BRAF targeted therapies like vemurafenib, an opportunity might exist to mitigate innate cellular immune escape mechanisms. We hypothesize that vemurafenib is an immunosensitizing agent that induces MAPK pathway de-regulation and sensitizes tumors to T-cell mediated lysis. We treated a human glioma cell line that carries a BRAF V600E mutation (DBTRG-05MG) with decitabine to uncover an antigenic target for NY-ESO-1 transduced T-cells. Tumor cell lysis was assessed using the xCELLigence Real-Time Cell Analyzer system. The Seahorse XF Extracellular Flux Analyzer was used to measure bioenergetic pathway fluctuation with BRAF inhibition. Cytotoxicity data demonstrated a dose-dependent enhancement of tumor cytolysis throughout the 48-hour assay that was not attributable to BRAF inhibition alone. With one effector cell per tumor cell, a 19.95% increase in lysis was found at three hours when cells were treated with the IC20 concentration of vemurafenib versus those untreated (*P= .0028, Student’s t-test). With 2.5 effector cells per tumor cell, cytolysis increased by 25.2% (*P= .0098), and by 40.52% (*P= .0081) with 5 effector cells per tumor cell. Vemurafenib treatment of tumors induced a reduction in the basal, ATP-linked, and maximal oxygen consumption rate (OCR), whereas T-cells co-cultured with vemurafenib treated tumor cells displayed an increase in aerobic and glycolytic metabolism. These results support an innovative, feasible treatment for BRAF mutant tumors. In a competition for metabolic fuel, the cytotoxic advantage for T-cells may be explained by reduced tumor consumption and increased availability of metabolic substrates in the tumor environment. Using the Nanostring Pathways Panel, we are also seeking to identify how vemurafenib induces oncogenic pathway de-regulation, which may provide insight on plausible treatments for metabolically abnormal tumors.
Source: Neuro-Oncology
Institutions: University of California, Los Angeles, UCLA Health
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2899833192