KRAS mutations hinder therapeutic efficacy of epidermal growth factor receptor (EGFR)-specific monoclonal antibodies cetuximab and panitumumab-based immunotherapy of EGFR+ cancers. Although cetuximab inhibits KRAS-mutated cancer cell growth in vitro by natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), KRAS-mutated colorectal carcinoma (CRC) cells escape NK cell immunosurveillance in vivo. To overcome this limitation, we used cetuximab and panitumumab to redirect Fc gamma chimeric receptor (CR) T cells against KRAS-mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fc gamma-CR constructs including CD16(158F)-CR, CD16(158V)-CR, CD32(131H)-CR, and CD32(131R)-CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32(131H)-CR (83.5 +/- 9.5) and CD32(131R)-CR (77.7 +/- 13.2) were significantly higher than those expressing with CD16(158F)-CR (30.3 +/- 10.2) and CD16(158V)-CR (51.7 +/- 13.7) (p < 0.003). CD32(131R)-CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16(158V)-CR T cells released high levels of interferon gamma (IFN gamma = 1,145.5 pg/ml +/- 16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNF alpha = 614 pg/ml +/- 21 pg/ml, p < 0.001) upon incubation with cetuximab-opsonized HCT116 cells. Moreover, only CD16(158V)-CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS-mutated cells in vitro. CD16(158V)-CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17-SCID mice in vivo. Thus, CD16(158V)-CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS-mutated CRC immunotherapies.

Arriga, R., Caratelli, S., Lanzilli, G., Ottaviani, A., Cenciarelli, C., Sconocchia, T., et al. (2020). CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab. INTERNATIONAL JOURNAL OF CANCER [10.1002/ijc.32618].

CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab

Caratelli S.;Ottaviani A.;Roselli M.;Lauro D.;Coppola A.;
2020-05-01

Abstract

KRAS mutations hinder therapeutic efficacy of epidermal growth factor receptor (EGFR)-specific monoclonal antibodies cetuximab and panitumumab-based immunotherapy of EGFR+ cancers. Although cetuximab inhibits KRAS-mutated cancer cell growth in vitro by natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), KRAS-mutated colorectal carcinoma (CRC) cells escape NK cell immunosurveillance in vivo. To overcome this limitation, we used cetuximab and panitumumab to redirect Fc gamma chimeric receptor (CR) T cells against KRAS-mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fc gamma-CR constructs including CD16(158F)-CR, CD16(158V)-CR, CD32(131H)-CR, and CD32(131R)-CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32(131H)-CR (83.5 +/- 9.5) and CD32(131R)-CR (77.7 +/- 13.2) were significantly higher than those expressing with CD16(158F)-CR (30.3 +/- 10.2) and CD16(158V)-CR (51.7 +/- 13.7) (p < 0.003). CD32(131R)-CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16(158V)-CR T cells released high levels of interferon gamma (IFN gamma = 1,145.5 pg/ml +/- 16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNF alpha = 614 pg/ml +/- 21 pg/ml, p < 0.001) upon incubation with cetuximab-opsonized HCT116 cells. Moreover, only CD16(158V)-CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS-mutated cells in vitro. CD16(158V)-CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17-SCID mice in vivo. Thus, CD16(158V)-CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS-mutated CRC immunotherapies.
mag-2020
Online ahead of print
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/06 - ONCOLOGIA MEDICA
Settore MED/09 - MEDICINA INTERNA
Settore CHIM/08 - CHIMICA FARMACEUTICA
Settore MED/13 - ENDOCRINOLOGIA
English
Con Impact Factor ISI
Fc gamma CR T cells; KRAS-mutated CRC; anti-EGFR mAb; immunotherapy; polymorphisms
Arriga, R., Caratelli, S., Lanzilli, G., Ottaviani, A., Cenciarelli, C., Sconocchia, T., et al. (2020). CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab. INTERNATIONAL JOURNAL OF CANCER [10.1002/ijc.32618].
Arriga, R; Caratelli, S; Lanzilli, G; Ottaviani, A; Cenciarelli, C; Sconocchia, T; Spagnoli, Gc; Iezzi, G; Roselli, M; Lauro, D; Coppola, A; Dotti, G; Ferrone, S; Sconocchia, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/224204
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