title: Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma.
abstract: OBJECTIVE
  The human endogenous retrovirus (HERV-K) envelope (env) protein is a tumor-associated antigen (TAA) expressed on melanoma but not normal cells. This study was designed to engineer a chimeric antigen receptor (CAR) on T-cell surface, such that they target tumors in advanced stages of melanoma.
  
  
  METHODS
  Expression of HERV-K protein was analyzed in 220 melanoma samples (with various stages of disease) and 139 normal organ donor tissues using immunohistochemical (IHC) analysis. HERV-K env-specific CAR derived from mouse monoclonal antibody was introduced into T cells using the transposon-based Sleeping Beauty (SB) system. HERV-K env-specific CAR(+) T cells were expanded ex vivo on activating and propagating cells (AaPC) and characterized for CAR expression and specificity. This includes evaluating the HERV-K-specific CAR(+) T cells for their ability to kill A375-SM metastasized tumors in a mouse xenograft model.
  
  
  RESULTS
  We detected HERV-K env protein on melanoma but not in normal tissues. After electroporation of T cells and selection on HERV-K(+) AaPC, more than 95% of genetically modified T cells expressed the CAR with an effector memory phenotype and lysed HERV-K env(+) tumor targets in an antigen-specific manner. Even though there is apparent shedding of this TAA from tumor cells that can be recognized by HERV-K env-specific CAR(+) T cells, we observed a significant antitumor effect.
  
  
  CONCLUSIONS
  Adoptive cellular immunotherapy with HERV-K env-specific CAR(+) T cells represents a clinically appealing treatment strategy for advanced-stage melanoma and provides an approach for targeting this TAA on other solid tumors.
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas. University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors.forename: Janani
authors.initials: J
authors.lastname: Krishnamurthy
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Rabinovich
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tiejuan
authors.initials: T
authors.lastname: Mi
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kirsten C
authors.initials: KC
authors.lastname: Switzer
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Simon
authors.initials: S
authors.lastname: Olivares
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sourindra N
authors.initials: SN
authors.lastname: Maiti
authors.affiliation: Michale E. Keeling Center for Comparative Medicine and Research, The University of Texas MD Anderson Cancer Center, Bastrop, Texas.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Plummer
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Harjeet
authors.initials: H
authors.lastname: Singh
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pappanaicken R
authors.initials: PR
authors.lastname: Kumaresan
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Huls
authors.affiliation: Viral Oncology, Biosciences Division, Center for Cancer and Metabolism, SRI International, Menlo Park, California.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang-Johanning
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas. University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. ljncooper@mdanderson.org.
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
mesh_terms: D000818:Animals; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008545:Melanoma / Q000276:immunology / Q000821:virology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000637:transplantation*; D014764:Viral Proteins / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C406149:HERV-K cORF protein, Human endogenous retrovirus K; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins
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