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IL-2, IL-15 and IL-21 expand T cells for targeted adoptive therapy

  • Zhenjiang Liu1,
  • Qingda Meng1,
  • Markus Maeurer1,
  • Elena Rangelova1,
  • Thomas Poiret1,
  • Rebecca Robertson1,
  • Aditya Ambati1,
  • Lalit Rane1,
  • Jiri Bartek1,
  • Caroline Verbeke1,
  • Oscar Persson1,
  • Matthias Löhr1,
  • Ralf Segersvärd1 and
  • Ernest Dodoo1
Journal for ImmunoTherapy of Cancer20153(Suppl 2):P31

Published: 4 November 2015


TAAT cellsIL-2IL-15IL-21adoptive T cell therapy


Expansion of antigen-specific T cells, from peripheral blood specific for tumor-associated antigens (TAAs) is a prerequisite for the advanced cellular therapy. Such antigen-specific T cells should express a Th1-functional phenotype and are able to enter tumor-tissue. We identified a cytokine cocktail, comprised of IL-2, IL-15 and IL-21 that drives antigen-specific T cells from peripheral blood mononuclear cells to tumor-associated antigens.

Materials and methods

20 blood samples (3 from health donors, 11 from glioma patients and 6 from pancreatic cancer patients) were collected, T cells were expanded using the cytokine cocktail IL-2/IL-15/IL-21 and TAAs, e.g. NY-ESO-1 or infectious antigens, e.g. CMV pp65 within 18-21 days. Intracellular Cytokine Staining (ICS) was used to detect antigen-specific immune responses by combining CD3, CD4 and CD8 markers with IL-2, TNF-α, IFN-γ production. Chemokine markers like CCR4, CCR6 or CXCR3 were used for phenotyping distinguishing Th1 and Th2 subtypes in CD4+ T cells, as well as in CD3+, CD4-CD8- (double-negative) T cell subsets. T cell memory phenotypes were defined by CCR7 and CD45RA staining. Tetramer (NY-ESO-1 or CMV specific) staining were used to show expansion of antigen specific T cells using a panel of mutant MHC class I tetramer molecules that allow to gauge for high, intermediate and low-affinity T cell populations imposed by interference of the MHC class I heavy chain with the CD8α binding site.


T cells from peripheral blood could be expanded (up to 10e10 cells) using IL-2, IL-15 and IL-21 and TAA-specific CD8, CD4 and CD3+, CD4-CD8-T cells could reliably be expanded defined by intracellular cytokine staining. In general, Th1 cells (CCR4-CXCR3+CCR6-) could be readily expanded along with (i.e. from 22.2% to 92.1%) along with increased expression of CXCR3 in both CD8+ and CD4+ T cells that enables increased access to tumor tissue. MHC class I-reactive T cells, directed against single T cell epitopes could be observed in up to 10% of CD8+, NY-ESO-1 specific T cells with a strong expansion of ‘high affinity’ T cells defined by i) mutant tetramers that interfere with CD8 engagement and ii) TAA-reactive T cells in the CD3+, CD4-CD8-double negative T cell subset.


T cells from peripheral blood samples can be reliably and successfully expanded in IL-2, IL-15 and IL-21, they show high affinity TCR – MHC class I/peptide engagement, a Th1-cytokine production pattern and increased CXCR3 expressing allowing T cell access into tissues. A Phase I clinical trial to target TAAs in patients with glioblastoma or pancreatic cancer will soon start at Karolinska using IL-2/IL-15/IL-21 and TAA-expanded T cells.

Authors’ Affiliations

Karolinska Institutet, Stockholm, Sweden


© Liu et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.