title: Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation.
abstract: Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic nonsynonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T-cell receptor (TCR) that is specific for a single AAS.
  
  
  
  By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy.
  
  
  
  When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intratumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T-cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar.
  
  
  
  Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer, but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape. Clin Cancer Res; 22(11); 2734-43. ©2015 AACRSee related commentary by Liu, p. 2602.
authors.affiliation: Institute of Immunology, Charité, Campus Buch, Berlin, Germany. matthias.leisegang@mdc-berlin.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Leisegang
authors.affiliation: Department of Pathology, The University of Chicago, Illinois.
authors.forename: Boris
authors.initials: B
authors.lastname: Engels
authors.affiliation: Department of Pathology, The University of Chicago, Illinois.
authors.forename: Karin
authors.initials: K
authors.lastname: Schreiber
authors.affiliation: Department of Medicine, The University of Chicago, Illinois.
authors.forename: Poh Yin
authors.initials: PY
authors.lastname: Yew
authors.affiliation: Department of Medicine, The University of Chicago, Illinois.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.affiliation: Department of Pathology, The University of Chicago, Illinois.
authors.forename: Christian
authors.initials: C
authors.lastname: Idel
authors.affiliation: Department of Pathology, The University of Chicago, Illinois.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arina
authors.affiliation: Department of Pathology, The University of Chicago, Illinois.
authors.forename: Jaikumar
authors.initials: J
authors.lastname: Duraiswamy
authors.affiliation: Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, The University of Chicago, Illinois.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Molecular Cell Biology and Gene Therapy, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Institute of Biology, Humboldt University Berlin, Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.affiliation: Department of Medicine, The University of Chicago, Illinois.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Institute of Immunology, Charité, Campus Buch, Berlin, Germany. Department of Pathology, The University of Chicago, Illinois.
authors.forename: Hans
authors.initials: H
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D024201:Bystander Effect; D045744:Cell Line, Tumor; D045142:Cross-Priming; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015316:Genetic Therapy; D016219:Immunotherapy, Adoptive; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D017354:Point Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D019139:Tumor Escape; D019892:eIF-2 Kinase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D019892:eIF-2 Kinase; C000605978:protein kinase R, mouse