EGFR806-CAR T cells selectively target a tumor-restricted EGFR epitope in glioblastoma.

Autor:	Ravanpay AC; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, U.S.A.; University of Washington, Department of Neurological Surgery, Seattle, WA, U.S.A., Gust J; University of Washington, Department of Neurology, Seattle, WA, U.S.A.; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, U.S.A., Johnson AJ; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, U.S.A., Rolczynski LS; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, U.S.A., Cecchini M; University of Washington, Department of Neurological Surgery, Seattle, WA, U.S.A., Chang CA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, U.S.A., Hoglund VJ; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, U.S.A., Mukherjee R; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, U.S.A., Vitanza NA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA, U.S.A.; University of Washington, Department of Pediatrics, Seattle, WA, U.S.A., Orentas RJ; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, U.S.A.; University of Washington, Department of Pediatrics, Seattle, WA, U.S.A., Jensen MC; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, U.S.A.; University of Washington, Department of Pediatrics, Seattle, WA, U.S.A.; University of Washington, Department of Bioengineering, Seattle, WA, U.S.A.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2019 Dec 17; Vol. 10 (66), pp. 7080-7095. Date of Electronic Publication: 2019 Dec 17 (Print Publication: 2019).
DOI:	10.18632/oncotarget.27389
Abstrakt:	Targeting solid tumor antigens with chimeric antigen receptor (CAR) T cell therapy requires tumor specificity and tolerance toward variability in antigen expression levels. Given the relative paucity of unique cell surface proteins on tumor cells for CAR targeting, we have focused on identifying tumor-specific epitopes that arise as a consequence of target protein posttranslational modification. We designed a CAR using a mAb806-based binder, which recognizes tumor-specific untethered EGFR. The mAb806 epitope is also exposed in the EGFRvIII variant transcript. By varying spacer domain elements of the CAR, we structurally tuned the CAR to recognize low densities of EGFR representative of non-gene amplified expression levels in solid tumors. The appropriately tuned short-spacer 2nd generation EGFR806-CAR T cells showed efficient in vitro cytokine secretion and glioma cell lysis, which was competitively blocked by a short peptide encompassing the mAb806 binding site. Unlike the nonselective Erbitux-based CAR, EGFR806-CAR T cells did not target primary human fetal brain astrocytes expressing wild-type EGFR, but showed a similar level of activity compared to Erbitux-CAR when the tumor-specific EGFRvIII transcript variant was overexpressed in astrocytes. EGFR806-CAR T cells successfully treated orthotopic U87 glioma implants in NSG mice, with 50% of animals surviving to 90 days. With additional IL-2 support, all tumors were eradicate without recurrence after 90 days. In a novel human induced pluripotent stem cell (iPSC)-derived teratoma xenograft model, EGFR806-CAR T cells infiltrated but were not activated in EGFR+ epidermal cell nests as assessed by Granzyme B expression. These results indicate that EGFR806-CAR T cells effectively and selectively target EGFR-expressing tumor cells. Competing Interests: CONFLICTS OF INTEREST Dr Orentas conducts consulting and sponsored research for Miltenyi Biotec, Inc. Dr Jensen has received grants and personal fees from Juno Therapeutics, a Celgene Company, during the conduct of the study but outside the submitted work. In addition, Dr Jensen holds a patent “Defined Composition Gene Modified T Cell Products”, with royalties paid to Juno Therapeutics. The remaining authors declare no conflicts of interest. (Copyright: © 2019 Ravanpay et al.)
Databáze:	MEDLINE
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