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T lymphocyte engineering with cytokine nanogels for enhanced cancer immunotherapy
© Tang et al. 2015
Published: 4 November 2015
Adoptive cell transfer (ACT) with autologous tumor-reactive T cells is a promising strategy in cancer immunotherapy, but treatment of solid tumors is limited by the rapid decline in function of the transplanted T cells. In order to maintain high numbers of viable antigen-specific cytotoxic T cells in tumors, co-administration of supporting immunostimulant agents together with transferred cells is often necessary in clinical practice. However, the high systemic doses of such agents needed to enhance T cell functionality can also result in serious side effects.
Here, we developed a carrier-free strategy to deliver cytokines specifically to adoptively transferred T cells for cancer immunotherapy. IL-2-Fc or an IL-15 superagonist were chemically cross-linked with a disulfide linker to form protein nanogels (NGs), which were conjugated to the plasma membrane of ACT T cells.
These NGs had exceptionally high loading of cytokines (~70 wt%) and released native protein in physiological conditions in a sustained manner through breakdown of the degradable disulfide linker in response to the activated T cell surface reduction activity. Cytokine-NGs were chemically conjugated onto the plasma membrane of donor T cells, enabling continuous pseudo-autocrine release of cytokine for stimulation of transferred CD8+ T cells. Transferred pmel-1 CD8+ T cells with optimized number of NGs conjugated per cell showed enhanced expansion and long persistence in B16F10 tumor bearing mice. Quantification of transferred Thy1.1+CD8+ T cells in tumors at Day 13 showed that T cells with conjugated cytokine-NGs expanded ~80 fold more than the T cells with systemically administered free cytokine.
We demonstrated that the cytokine-NG-T cell conjugation strategy could augment transferred T cell expansion efficiently and specifically in vivo, and thus improve the therapeutic efficacy. This T cell-NG “back pack” approach provides a readily generalizable strategy to provide autocrine protein drug support to donor cells to enhance the safety and efficacy of ACT.
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 (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.