In vivo proof of concept of adoptive immunotherapy for hepatocellular carcinoma using allogeneic suicide gene-modified killer cells.
Cell therapy based on alloreactivity has completed clinical proof of concept against hematological malignancies. However, the efficacy of alloreactivity as a therapeutic approach to treat solid tumors is unknown. Using cell culture and animal models, we aimed to investigate the efficacy and safety of allogeneic suicide gene-modified killer cells as a cell-based therapy for hepatocellular carcinoma (HCC), for which treatment options are limited. Allogeneic killer cells from healthy donors were isolated, expanded, and phenotypically characterized. Antitumor cytotoxic activity and safety were studied using a panel of human or murine HCC cell lines engrafted in immunodeficient or immunocompetent mouse models. Human allogeneic suicide gene-modified killer cells (aSGMKCs) exhibit a high, rapid, interleukin-2-dependent, and non-major histocompatibility complex class I-restricted in vitro cytotoxicity toward human hepatoma cells, mainly mediated by natural killer (NK) and NK-like T cells. In vivo evaluation of this cell therapy product demonstrates a marked, rapid, and sustained regression of HCC. Preferential liver homing of effector cells contributed to its marked efficacy. Calcineurin inhibitors allowed preventing rejection of allogeneic lymphocytes by the host immune system without impairing their antitumor activity. Our results demonstrate proof of concept for aSGMKCs as immunotherapy for HCC and open perspectives for the clinical development of this approach.
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Current address: Transplantation and Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland.
Céline
C
Leboeuf
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
Laurent
L
Mailly
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China.
Tao
T
Wu
Institut de Recherche sur les Cancers de l'Appareil Digestif, Strasbourg, France.
Gaetan
G
Bour
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
Sarah
S
Durand
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
Nicolas
N
Brignon
Etablissement Français du Sang Bourgogne/Franche-Comté, UMR 1098, Besançon, France; Inserm, UMR 1098, Besançon, France; Université de Franche-Comté, UMR 1098, Besançon, France.
Christophe
C
Ferrand
Etablissement Français du Sang Bourgogne/Franche-Comté, UMR 1098, Besançon, France; Inserm, UMR 1098, Besançon, France; Université de Franche-Comté, UMR 1098, Besançon, France.
Christophe
C
Borg
Etablissement Français du Sang Bourgogne/Franche-Comté, UMR 1098, Besançon, France; Inserm, UMR 1098, Besançon, France; Université de Franche-Comté, UMR 1098, Besançon, France.
Pierre
P
Tiberghien
Department of Medicine II, University Medical Center, University of Freiburg, Freiburg, Germany.
Robert
R
Thimme
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépatodigestif, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire de Strasbourg, Strasbourg, France.
Patrick
P
Pessaux
Université de Strasbourg, Strasbourg, France; Institut de Recherche sur les Cancers de l'Appareil Digestif, Strasbourg, France; Pôle Hépatodigestif, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire de Strasbourg, Strasbourg, France.
Jacques
J
Marescaux
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépatodigestif, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire de Strasbourg, Strasbourg, France.
Thomas F
TF
Baumert
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire de Strasbourg, Strasbourg, France. Electronic address: eric.robinet@ihu_strasbourg.eu.
Eric
E
Robinet
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000628:therapy*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006367:HeLa Cells; D006801:Humans; D016219:Immunotherapy, Adoptive; D008113:Liver Neoplasms / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014184:Transplantation, Homologous / Q000379:methods*