Engineered T cells controlled by granulocyte colony-stimulating factor eradicate murine melanoma without lymphodepletion or interleukin-2
- 1Trev and Joyce Deeley Research Centre, BC Cancer; Victoria, British Columbia, Canada
Abstract
Tumour-infiltrating lymphocyte (TIL) therapy can be effective against metastatic melanoma, including immune checkpoint-resistant disease, but current protocols require lymphodepletion and high-dose interleukin-2 (IL-2), which can cause substantial toxicity. To overcome this limitation, we engineered a chimeric receptor, G2R, that generates an IL-2-like proliferative signal in response to granulocyte colony-stimulating factor (G-CSF), a well-tolerated cytokine widely used in oncology. Human T cells expressing G2R expanded in vitro in response to G-CSF in place of IL-2 or interleukin-15 (IL-15), and the three cytokines induced broadly similar intracellular signalling and cytokine secretion profiles. In immune-competent mice bearing established B16-F10 melanoma, adoptive transfer of G2R-expressing, tumour-reactive CD8+ T cells followed by systemic G-CSF treatment induced profound T cell expansion. This was accompanied by complete, durable tumour regression in over 75% of animals without the need for lymphodepletion, exogenous IL-2 or any other therapy. G-CSF treatment induced transient neutrophil expansion in peripheral blood but no increase in intratumoural neutrophils or macrophages. G2R-expressing memory T cells persisted long-term and could be re-expanded upon G-CSF re-treatment, enabling rejection of second tumour challenges. Thus, G-CSF can be repurposed to enable clinician-controlled anti-tumour T cell responses of profound magnitude, efficacy and durability, an approach that is readily translatable to humans.
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BibTeX
@misc{preshaw2026engineered,
title = {{Engineered T cells controlled by granulocyte colony-stimulating factor eradicate murine melanoma without lymphodepletion or interleukin-2}},
author = {S. C. Preshaw and M. E. Fuller and C. J. Powell and K. Milne and K. Sewell and M. B. Adamson and A. Pearson-Lund and M. Joly and S. Goodwin and N. Shakerian and N. J. S. Taylor and M. Z. Xu and T. Bryce and D. Klassen and J. C. Smazynski and M. J. Boulanger and B. H. Nelson},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.760485},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.760485v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Engineered T cells controlled by granulocyte colony-stimulating factor eradicate murine melanoma without lymphodepletion or interleukin-2
AU - S. C. Preshaw
AU - M. E. Fuller
AU - C. J. Powell
AU - K. Milne
AU - K. Sewell
AU - M. B. Adamson
AU - A. Pearson-Lund
AU - M. Joly
AU - S. Goodwin
AU - N. Shakerian
AU - N. J. S. Taylor
AU - M. Z. Xu
AU - T. Bryce
AU - D. Klassen
AU - J. C. Smazynski
AU - M. J. Boulanger
AU - B. H. Nelson
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.760485
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.760485v1
AB - Tumour-infiltrating lymphocyte (TIL) therapy can be effective against metastatic melanoma, including immune checkpoint-resistant disease, but current protocols require lymphodepletion and high-dose interleukin-2 (IL-2), which can cause substantial toxicity. To overcome this limitation, we engineered a chimeric receptor, G2R, that generates an IL-2-like proliferative signal in response to granulocyte colony-stimulating factor (G-CSF), a well-tolerated cytokine widely used in oncology. Human T cells expressing G2R expanded in vitro in response to G-CSF in place of IL-2 or interleukin-15 (IL-15), and the three cytokines induced broadly similar intracellular signalling and cytokine secretion profiles. In immune-competent mice bearing established B16-F10 melanoma, adoptive transfer of G2R-expressing, tumour-reactive CD8+ T cells followed by systemic G-CSF treatment induced profound T cell expansion. This was accompanied by complete, durable tumour regression in over 75% of animals without the need for lymphodepletion, exogenous IL-2 or any other therapy. G-CSF treatment induced transient neutrophil expansion in peripheral blood but no increase in intratumoural neutrophils or macrophages. G2R-expressing memory T cells persisted long-term and could be re-expanded upon G-CSF re-treatment, enabling rejection of second tumour challenges. Thus, G-CSF can be repurposed to enable clinician-controlled anti-tumour T cell responses of profound magnitude, efficacy and durability, an approach that is readily translatable to humans.
ER -