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Front. Immunol. | doi: 10.3389/fimmu.2019.00319

Peptide Super-agonist enhances T-cell Responses to Melanoma

  • 1Cardiff University, United Kingdom
  • 2University of Copenhagen, Denmark
  • 3Immunocore (United Kingdom), United Kingdom

Recent immunotherapeutic approaches using adoptive cell therapy, or checkpoint blockade, have demonstrated the powerful anti-cancer potential of CD8 cytotoxic T-lymphocytes (CTL). While these approaches have shown great promise, they are only effective in some patients with some cancers. The potential power, and relative ease, of therapeutic vaccination against tumour associated antigens (TAA) that can be present in many different cancers has been a long sought-after approach for harnessing the discriminating sensitivity of CTL to treat cancer that has seen recent renewed interest following cancer vaccination successes using unique tumour neoantigens. Unfortunately, results with TAA-targeted ‘universal’ cancer vaccines (UCV) have been largely disappointing. Infectious disease models have demonstrated that T-cell clonotypes that recognise the same antigen should not be viewed as being equally effective. Extrapolation of this notion to UCV would suggest that the quality of response in terms of the T-cell receptor (TCR) clonotypes induced might be more important than the quantity of the response. Unfortunately, there is little opportunity to assess the effectiveness of individual T-cell clonotypes in vivo. Here, we identified effective, persistent T-cell clonotypes in an HLA A*0201+ patient following successful tumour infiltrating lymphocyte (TIL) therapy. One such T-cell clone was used to generate super-agonist altered peptide ligands (APLs). Further refinement produced an APL that was capable of inducing T-cells in greater magnitude, and with improved effectiveness, from the blood of all 12 healthy donors tested. Importantly, this APL also induced T-cells from melanoma patient blood that exhibited superior recognition of the patient’s own tumour compared to those induced by the natural antigen sequence. These results suggest that use of APL to skew the clonotypic quality of T-cells induced by cancer vaccination could provide a promising avenue in the hunt for the UCV ‘magic bullet’.

Keywords: T cell, T cell receptor, Melanoma, Cancer, altered peptide ligand, Vaccine candidate, Tumour infiltrating lymphocyte therapy

Received: 12 Jun 2018; Accepted: 06 Feb 2019.

Edited by:

Clemencia Pinilla, Torrey Pines Institute for Molecular Studies, United States

Reviewed by:

Brian M. Baker, University of Notre Dame, United States
David Escors, University College London, United Kingdom
Valérie Dutoit, Université de Genève, Switzerland  

Copyright: © 2019 Galloway, Dolton, Attaf, Wall, Fuller, Rius, Bianchi, Theaker, Svane, Donia, Szomolay, Cole, Rizkallah and Sewell. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Andrew K. Sewell, Cardiff University, Cardiff, United Kingdom, sewellak@cardiff.ac.uk