Targeting cancer-specific mutations by T cell receptor gene therapy

Thomas Blankenstein; Matthias Leisegang; Wolfgang Uckert; Hans Schreiber

doi:10.1016/j.coi.2015.02.005

Targeting cancer-specific mutations by T cell receptor gene therapy

Curr Opin Immunol. 2015 Apr:33:112-9. doi: 10.1016/j.coi.2015.02.005. Epub 2015 Feb 27.

Authors

Thomas Blankenstein¹, Matthias Leisegang², Wolfgang Uckert³, Hans Schreiber⁴

Affiliations

¹ Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany; Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany. Electronic address: [email protected].
² Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany.
³ Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany; Institute of Biology, Humboldt University Berlin, 10115 Berlin, Germany.
⁴ 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.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Antigens, Neoplasm / genetics
Antigens, Neoplasm / immunology
Antigens, Neoplasm / metabolism
Epitopes, T-Lymphocyte / genetics
Epitopes, T-Lymphocyte / immunology
Epitopes, T-Lymphocyte / metabolism
Histocompatibility Antigens Class I / immunology
Histocompatibility Antigens Class I / metabolism
Humans
Immunotherapy, Adoptive* / adverse effects
Immunotherapy, Adoptive* / methods
Mutation*
Neoplasms / genetics*
Neoplasms / immunology
Neoplasms / therapy*
Protein Binding
Receptors, Antigen, T-Cell / genetics*
Receptors, Antigen, T-Cell / metabolism
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
T-Cell Antigen Receptor Specificity / genetics
T-Cell Antigen Receptor Specificity / immunology
T-Lymphocyte Subsets / immunology*
T-Lymphocyte Subsets / metabolism*
Treatment Outcome

Substances

Antigens, Neoplasm
Epitopes, T-Lymphocyte
Histocompatibility Antigens Class I
Receptors, Antigen, T-Cell
Recombinant Fusion Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding