title: TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors.
abstract: The success in recent clinical trials using T cell receptor (TCR)-genetically engineered T cells to treat melanoma has encouraged the use of this approach toward other malignancies and viral infections. Although hepatitis C virus (HCV) infection is being treated with a new set of successful direct anti-viral agents, potential for virologic breakthrough or relapse by immune escape variants remains. Additionally, many HCV+ patients have HCV-associated disease, including hepatocellular carcinoma (HCC), which does not respond to these novel drugs. Further exploration of other approaches to address HCV infection and its associated disease are highly warranted. Here, we demonstrate the therapeutic potential of PBL-derived T cells genetically engineered with a high-affinity, HLA-A2-restricted, HCV NS3:1406-1415-reactive TCR. HCV1406 TCR-transduced T cells can recognize naturally processed antigen and elicit CD8-independent recognition of both peptide-loaded targets and HCV+ human HCC cell lines. Furthermore, these cells can mediate regression of established HCV+ HCC in vivo. Our results suggest that HCV TCR-engineered antigen-reactive T cells may be a plausible immunotherapy option to treat HCV-associated malignancies, such as HCC.
authors: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL, 60153, USA.
authors: Timothy T
authors: TT
authors: Spear
authors: Department of Surgery, University of Chicago, Chicago, IL, 60637, USA.|Department of Surgery, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors: Glenda G
authors: GG
authors: Callender
authors: Department of Surgery, University of Chicago, Chicago, IL, 60637, USA.
authors: Jeffrey J
authors: JJ
authors: Roszkowski
authors: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL, 60153, USA.|Department of Surgery, Medical University of South Carolina, Charleston, SC, 29415, USA.
authors: Kelly M
authors: KM
authors: Moxley
authors: Flow Cytometry Core Facility, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, 60153, USA.
authors: Patricia E
authors: PE
authors: Simms
authors: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL, 60153, USA.
authors: Kendra C
authors: KC
authors: Foley
authors: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL, 60153, USA.
authors: David C
authors: DC
authors: Murray
authors: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL, 60153, USA.|Department of Surgery, Medical University of South Carolina, Charleston, SC, 29415, USA.
authors: Gina M
authors: GM
authors: Scurti
authors: Department of Surgery, Medical University of South Carolina, Charleston, SC, 29415, USA.
authors: Mingli
authors: M
authors: Li
authors: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL, 60153, USA.
authors: Justin T
authors: JT
authors: Thomas
authors: Department of Surgery, University of Chicago, Chicago, IL, 60637, USA.
authors: Alexander
authors: A
authors: Langerman
authors: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, 29415, USA.|Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29415, USA.
authors: Elizabeth
authors: E
authors: Garrett-Mayer
authors: Department of Surgery, Medical University of South Carolina, Charleston, SC, 29415, USA.|Biotherapy Center and Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.
authors: Yi
authors: Y
authors: Zhang
authors: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Maywood, IL, 60153, USA. mnishimura@luc.edu.|Department of Surgery, University of Chicago, Chicago, IL, 60637, USA. mnishimura@luc.edu.|Department of Surgery, Medical University of South Carolina, Charleston, SC, 29415, USA. mnishimura@luc.edu.
authors: Michael I
authors: MI
authors: Nishimura
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000628:therapy*; D045744:Cell Line, Tumor; D019672:Genes, T-Cell Receptor / Q000502:physiology*; D005818:Genetic Engineering; D015789:HLA-A2 Antigen / Q000276:immunology; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D007167:Immunotherapy; D008113:Liver Neoplasms / Q000209:etiology / Q000628:therapy*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D015789:HLA-A2 Antigen; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: Adoptive cell transfer; Cancer; Hepatitis C virus; Hepatocellular carcinoma; T cell; T cell receptor