HER2 CAR-T cells eradicate uveal melanoma and T-cell therapy–resistant human melanoma in IL2 transgenic NOD/SCID IL2 receptor knockout mice
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HER2 CAR-T cells eradicate uveal melanoma and T-cell therapy–resistant human melanoma in IL2 transgenic NOD/SCID IL2 receptor knockout mice. / Forsberg, Elin M.V.; Lindberg, Mattias F.; Jespersen, Henrik; Alsen, Samuel; Bagge, Roger Olofsson; Donia, Marco; Svane, Inge Marie; Nilsson, Ola; Ny, Lars; Nilsson, Lisa M.; Nilsson, Jonas A.
In: Cancer Research, Vol. 79, No. 5, 2019, p. 899-904.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - HER2 CAR-T cells eradicate uveal melanoma and T-cell therapy–resistant human melanoma in IL2 transgenic NOD/SCID IL2 receptor knockout mice
AU - Forsberg, Elin M.V.
AU - Lindberg, Mattias F.
AU - Jespersen, Henrik
AU - Alsen, Samuel
AU - Bagge, Roger Olofsson
AU - Donia, Marco
AU - Svane, Inge Marie
AU - Nilsson, Ola
AU - Ny, Lars
AU - Nilsson, Lisa M.
AU - Nilsson, Jonas A.
PY - 2019
Y1 - 2019
N2 - 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), for example, 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 IL2 receptor gamma (NOG) knockout mouse strain transgenic for human IL2. 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 T-cell transfer (ACT) of autologous TILs. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. In addition, our data highlight the use of IL2 transgenic NOG mice as models to prove efficacy of CAR-T-cell products, possibly even in a personalized manner. Significance: These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
AB - 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), for example, 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 IL2 receptor gamma (NOG) knockout mouse strain transgenic for human IL2. 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 T-cell transfer (ACT) of autologous TILs. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. In addition, our data highlight the use of IL2 transgenic NOG mice as models to prove efficacy of CAR-T-cell products, possibly even in a personalized manner. Significance: These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
U2 - 10.1158/0008-5472.CAN-18-3158
DO - 10.1158/0008-5472.CAN-18-3158
M3 - Journal article
C2 - 30622115
AN - SCOPUS:85062264623
VL - 79
SP - 899
EP - 904
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 5
ER -
ID: 230250544