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Caratelli, S; Arriga, R; Sconocchia, T; Ottaviani, A; Lanzilli, G; Pastore, D; Cenciarelli, C; Venditti, A; Del Principe, MI; Lauro, D; Landoni, E; Du, HW; Savoldo, B; Ferrone, S; Dotti, G; Sconocchia, G.
In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab
INT J CANCER. 2020; 146(1): 236-247.
Web of Science PubMed FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Sconocchia Tommaso
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Abstract:
Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the Fc gamma RIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the Fc gamma RII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A(131R)-chimeric receptor (CR), and those engineered with the low-affinity CD16(158F)-CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A(131R)-CR T cells was 74 +/- 10%, whereas the percentage of CD16(158F)-CR T cells was 46 +/- 15%. Only CD32A(131R)-CR T cells bound panitumumab. CD32A(131R)-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16(158F)-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116(Fc gamma R+) cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A(131R)-CR on T cells by cetuximab or panitumumab and CD16(158F)-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fc gamma-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fc gamma-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A(131R)-CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR.

Find related publications in this database (Keywords)
CAR T cells
panitumumab
cetuximab
EGFR
breast cancer
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