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

• Published in: International journal of cancer 2020-05, Vol.146 (9), p.2531-2538
• Main Authors: Arriga, Roberto, Caratelli, Sara, Lanzilli, Giulia, Ottaviani, Alessio, Cenciarelli, Carlo, Sconocchia, Tommaso, Spagnoli, Giulio C., Iezzi, Giandomenica, Roselli, Mario, Lauro, Davide, Coppola, Andrea, Dotti, Gianpietro, Ferrone, Soldano, Sconocchia, Giuseppe
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Immunological - pharmacology; anti‐EGFR mAb; Apoptosis; Cancer; CD16 antigen; Cell Proliferation; Cetuximab - pharmacology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Cytotoxicity; Drug Resistance, Neoplasm; Epidermal growth factor; Epidermal growth factor receptors; Fc gamma CR T cells; Humans; Immunosurveillance; Immunotherapy; Immunotherapy, Adoptive - methods; K-Ras protein; KRAS‐mutated CRC; Lymphocytes; Lymphocytes T; Male; Medical research; Mice; Mice, SCID; Monoclonal antibodies; Mutation; Natural killer cells; Opsonization; polymorphisms; Proto-Oncogene Proteins p21(ras) - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, IgG - genetics; Receptors, IgG - immunology; Targeted cancer therapy; Tumor Cells, Cultured; Tumor necrosis factor-α; Valine; Valine - genetics; Xenograft Model Antitumor Assays; γ-Interferon
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32618

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 Fcγ chimeric receptor (CR) T cells against KRAS‐mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fcγ‐CR constructs including CD16158F‐CR, CD16158V‐CR, CD32131H‐CR, and CD32131R‐CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32131H‐CR (83.5 ± 9.5) and CD32131R‐CR (77.7 ± 13.2) were significantly higher than those expressing with CD16158F‐CR (30.3 ± 10.2) and CD16158V‐CR (51.7 ± 13.7) (p