Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 10, Issue 430, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aao2731
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Funding
- University Cancer Research Fund at University of North Carolina, Lineberger Comprehensive Cancer Center
- Il Fondo di Gio Onlus
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The heterogeneous expression of tumor-associated antigens limits the efficacy of chimeric antigen receptor (CAR)redirected T cells (CAR-Ts) for the treatment of glioblastoma (GBM). We have found that chondroitin sulfate proteoglycan 4 (CSPG4) is highly expressed in 67% of the GBM specimens with limited heterogeneity. CSPG4 is also expressed on primary GBM-derived cells, grown in vitro as neurospheres (GBM-NS), which recapitulate the histopathology and molecular characteristics of primary GBM. CSPG4. CAR-Ts efficiently controlled the growth of GBM-NS in vitro and in vivo upon intracranial tumor inoculation. Moreover, CSPG4. CAR-Ts were also effective against GBM-NS with moderate to low expression of CSPG4. This effect was mediated by the in vivo up-regulation of CSPG4 on tumor cells, induced by tumor necrosis factor-alpha (TNF alpha) released by the microglia surrounding the tumor. Overall, the constitutive and TNF alpha-inducible expression of CSPG4 in GBM may greatly reduce the risk of tumor cell escape observed when targeted antigens are heterogeneously expressed on tumor cells.
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