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

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 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 < 0.003). CD32131R -CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16158V -CR T cells released high levels of interferon gamma (IFNγ = 1,145.5 pg/ml ±16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNFα = 614 pg/ml ± 21 pg/ml, p < 0.001) upon incubation with cetuximab-opsonized HCT116 cells. Moreover, only CD16158V -CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS-mutated cells in vitro. CD16158V -CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17-SCID mice in vivo. Thus, CD16158V -CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS-mutated CRC immunotherapies.

• Authors: Roberto Arriga, Sara Caratelli, Giulia Lanzilli, Alessio Ottaviani, Carlo Cenciarelli, Tommaso Sconocchia, Giulio C Spagnoli, Giandomenica Iezzi, Mario Roselli, Davide Lauro, Andrea Coppola, Gianpietro Dotti, Soldano Ferrone, Giuseppe Sconocchia
• Journal: International journal of cancer (Int J Cancer) Vol. 146 Issue 9 Pg. 2531-2538 (05 01 2020) ISSN: 1097-0215 [Electronic] United States
• PMID: 31396956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 UICC.

Chemical References

• Antineoplastic Agents, Immunological
• KRAS protein, human
• Receptors, Antigen, T-Cell
• Receptors, IgG
• Proto-Oncogene Proteins p21(ras)
• Valine
• Cetuximab

Topics

• Animals
• Antineoplastic Agents, Immunological (pharmacology)
• Apoptosis
• Cell Proliferation
• Cetuximab (pharmacology)
• Colorectal Neoplasms (genetics, immunology, pathology, therapy)
• Drug Resistance, Neoplasm
• Humans
• Immunotherapy, Adoptive (methods)
• Male
• Mice
• Mice, SCID
• Mutation
• Proto-Oncogene Proteins p21(ras) (genetics)
• Receptors, Antigen, T-Cell (immunology)
• Receptors, IgG (genetics, immunology)
• Tumor Cells, Cultured
• Valine (genetics)
• Xenograft Model Antitumor Assays