title: Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer.
abstract: OBJECTIVE
  The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide-MHC complexes can be targets for CAR T-cell therapy against solid tumors.
  
  
  METHODS
  We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP158-166peptide complexed with human leukocyte antigen (HLA)-A*02:01.
  
  
  RESULTS
  We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01+/AFP+while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP158-expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6).
  
  
  CONCLUSIONS
  This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. Clin Cancer Res; 23(2); 478-88. ©2016 AACR.
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Li
authors.initials: L
authors.lastname: Long
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Shon
authors.initials: S
authors.lastname: Green
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Bryan
authors.initials: B
authors.lastname: Zimdahl
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Lu
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Neal
authors.initials: N
authors.lastname: Cheng
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Lucas H
authors.initials: LH
authors.lastname: Horan
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Su
authors.initials: S
authors.lastname: Yan
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Juan
authors.initials: J
authors.lastname: Diaz
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Lu
authors.initials: L
authors.lastname: Jin
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Javier F
authors.initials: JF
authors.lastname: Morales
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Pengbo
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Lian-Xing
authors.initials: LX
authors.lastname: Liu
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Binnaz K
authors.initials: BK
authors.lastname: Staley
authors.affiliation: Department of Immuno-oncology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, California.|Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Priceman
authors.affiliation: Department of Immuno-oncology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, California.|Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.affiliation: Department of Immuno-oncology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, California.|Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California.
authors.forename: Vivien W
authors.initials: VW
authors.lastname: Chan
authors.affiliation: Eureka Therapeutics Inc., Emeryville, California. cheng.liu@eurekainc.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D056945:Hep G2 Cells; D006801:Humans; D007167:Immunotherapy; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D058990:Molecular Targeted Therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell; D000509:alpha-Fetoproteins