Targeting cancer-specific mutations by T cell receptor gene therapy.
The ease of sequencing the cancer genome, identifying all somatic mutations and grafting mutation-specific T cell receptor (TCR) genes into T cells for adoptive transfer allow, for the first time, a truly tumor-specific and effective therapy. Mutation-specific TCR gene therapy might achieve optimal efficacy with least possible toxicity. Recent clinical data confirm the long-standing evidence from experimental cancer models that antigens encoded by the tumor-specific somatic mutations are potentially the best targets for adoptive T cell therapy. Open questions are, how many somatic mutations create suitable epitopes, whether only individual-specific or also recurrent somatic mutations qualify as suitable epitopes and how neoantigen-specific TCRs are most efficiently obtained. Tumor heterogeneity needs to be considered; therefore, it will be important to identify immunogenic driver mutations that occurred early, are essential for cancer cell survival and present in all cancer cells.
Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany; Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany. Electronic address: tblanke@mdc-berlin.de.
Thomas
T
Blankenstein
Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany.
Matthias
M
Leisegang
Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany; Institute of Biology, Humboldt University Berlin, 10115 Berlin, Germany.
Wolfgang
W
Uckert
Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany; Department of Pathology, Committee on Immunology and Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637, USA.
Hans
H
Schreiber
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins