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Region Hovedstaden - en del af Københavns Universitetshospital
E-pub ahead of print

HER2 CAR-T cells eradicate uveal melanoma and T cell therapy-resistant human melanoma in interleukin-2 (IL-2) transgenic NOD/SCID IL-2 receptor knockout mice

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  • Elin Mv Forsberg
  • Mattias F Lindberg
  • Henrik Jespersen
  • Samuel Alsén
  • Roger Olofsson Bagge
  • Marco Donia
  • Inge Marie Svane
  • Ola Nilsson
  • Lars Ny
  • Lisa M Nilsson
  • Jonas A Nilsson
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Chimeric antigen receptors (CAR) can transmit signals akin to those from activated T cell receptors when bound to a cell surface target. CAR expressing T cells against CD19 can cause curative effects in leukemia and lymphoma and is approved for clinical use. However, no CAR-T therapy is currently approved for use in solid tumors. We hypothesize that the resistance of solid tumors to CAR-T can be overcome by similar means as those used to reactivate tumor-infiltrating T lymphocytes (TIL), e.g., by cytokines or immune checkpoint blockade. Here we demonstrate that CAR-T cells directed against HER2 can kill uveal and cutaneous melanoma cells in vitro and in vivo. Curative effects in vivo were only observed in xenografts grown in a NOD/SCID interleukin-2 (IL-2) receptor gamma (NOG) knockout mouse strain transgenic for human IL-2. The effect was target-specific, as CRISPR/Cas9-mediated disruption of HER2 in the melanoma cells abrogated the killing effect of the CAR-T cells. The CAR-T cells were also able to kill melanoma cells from patients resistant to adoptive cell transfer (ACT) of autologous TIL. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. Additionally, our data highlight the use of IL-2 transgenic NOG mice as models to prove efficacy of CAR-T cell products, possibly even in a personalized manner.

OriginalsprogEngelsk
TidsskriftCancer Research
ISSN0008-5472
DOI
StatusE-pub ahead of print - 8 jan. 2019

ID: 56254105