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• W2561869162 abstract "Adoptive therapy with chimeric antigen receptor-redirected T cells (CAR-Ts) remains challenging for the treatment of glioblastoma (GBM) because of the heterogeneous expression of targetable tumor antigens, which leads to the selection of antigen-loss variants. In addition, the emerging role of GBM-derived neurospheres (GBM-NS) as a critical cell subset in causing GBM recurrence highlights the need to eradicate these cells to achieve sustained responses. By exploiting a well-established culture system, we generated and expanded GBM-NS from 23 surgical samples, and tested them using flow cytometry for the expression of CSPG4, a membrane bound tumor antigen found to be overexpressed in GBM by mRNA profiling. We observed that 70% of GBM-NS displayed high expression of CSPG4 (from 71% to 99%), 17% moderate-high expression (from 51% to 70%), and 13% moderate-low expression (<50%). Based on these results, we hypothesized that CSPG4-specific CAR-Ts would represent a broadly applicable strategy for the treatment of GBM. We generated CSPG4. CAR-Ts, encoding the 4-1BB endodomain, from 6 healthy donors and tested them against 19 of the 23 generated GBM-NS that robustly grow in vitro. CSPG4.CAR-Ts efficiently eliminated all GBM-NS, with high to moderate-low CSPG4 expression, in co-culture experiments at E:T ratios ranging from 2:5 to 1:5 (0.2±0.5% and 0.6±0.9% residual GBM-NS, respectively). By contrast, GBM-NS continued to grow in the presence of control T cells (60.7±17.6% residual GBM-NS). CSPG4.CAR-Ts, but not control T cells, also rapidly proliferated in response to GBM-NS as evaluated by the CFSE assay. CSPG4. CAR-Ts showed a Th1 cytokine profile in response to GBM-NS, releasing significantly more IFN-γ (3593.8±1718.1 pg/ml/2×10^5 cells) and IL-2 (258.8±153.3 pg/ml/2×10^5 cells) than control T cells (1.8±2.5 and 0.9±1.2 pg/ml/2×10^5 cells, respectively). For the in vivo experiments we compared CSPG4.CAR-Ts encoding CD28, 4-1BB, or CD28-4-1BB co-stimulatory endodomains. Two GBM-NS with moderate-low and high CSPG4 expression, respectively were selected and transduced to express the FFluciferase gene to monitor the tumor growth by in vivo bioluminescence imaging. Both GBM-NS and T cells were intracranially injected in 5 wks old female nude mice. CSPG4.CAR-Ts were efficient in controlling tumor growth of both moderate-low and high CSPG4-expressing GBM-NS. We observed an early eradication of the tumor mass in high-CSPG4 expressing GBM-NS, and a significant improved survival in both mice bearing high or moderate-low CSPG4-expressing GBM-NS. CAR-Ts encoding 4-1BB were significantly more efficient than those encoding CD28 or CD28-4-1BB in prolonging tumor free survival (p=0.04). Our data suggest that CSPG4 is an attractive target for CAR-Ts in GBM and that the strategy we have shown to be effective in mice has the potential to be translated to a clinical setting." @default.
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• W2561869162 date "2016-05-01" @default.
• W2561869162 modified "2023-09-27" @default.
• W2561869162 title "507. Chondroitin Sulfate Proteoglycan 4 (CSPG4)-Redirected T Cells Eliminate Glioblastoma-Derived Neurospheres" @default.
• W2561869162 doi "https://doi.org/10.1016/s1525-0016(16)33316-0" @default.
• W2561869162 hasPublicationYear "2016" @default.
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