Therapeutic Targeting of Mesothelin with Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia
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- Quy Le
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Sommer Castro
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Thao Tang
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Anisha M. Loeb
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Tiffany Hylkema
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Cyd Nourigat McKay
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- LaKeisha Perkins
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Shivani Srivastava
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Lindsey Call
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Jenny Smith
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Amanda Leonti
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Rhonda Ries
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Laura Pardo
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Michael R. Loken
- 2Hematologics, Inc, Seattle, Washington.
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- Colin Correnti
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Salvatore Fiorenza
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Cameron J. Turtle
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Stanley Riddell
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Katherine Tarlock
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
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- Soheil Meshinchi
- 1Fred Hutchinson Cancer Research Center, Seattle, Washington.
説明
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>We previously identified mesothelin (MSLN) as highly expressed in a significant fraction of acute myeloid leukemia (AML) but entirely silent in normal hematopoiesis, providing a promising antigen for immunotherapeutic targeting that avoids hematopoietic toxicity. Given that T cells genetically modified to express chimeric antigen receptors (CAR) are effective at eradicating relapsed/refractory acute lymphocytic leukemia, we developed MSLN-directed CAR T cells for preclinical evaluation in AML.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>The variable light (VL) and heavy (VH) sequences from the MSLN-targeting SS1P immunotoxin were used to construct the single-chain variable fragment of the standard CAR containing 41-BB costimulatory and CD3Zeta stimulatory domains. The preclinical efficacy of MSLN CAR T cells was evaluated against AML cell lines and patient samples expressing various levels of MSLN in vitro and in vivo.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>We demonstrate that MSLN is expressed on the cell surface of AML blasts and leukemic stem cell–enriched CD34+CD38− subset, but not on normal hematopoietic stem and progenitor cells (HSPC). We further establish that MSLN CAR T cells are highly effective in eliminating MSLN-positive AML cells in cell line– and patient-derived xenograft models. Importantly, MSLN CAR T cells can target and eradicate CD34+CD38− cells without impacting the viability of normal HSPCs. Finally, we show that CAR T-cell functionality can be improved by inhibition of the ADAM17 metalloprotease that promotes shedding of MSLN.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>These findings demonstrate that MSLN is a viable target for CAR T-cell therapy in AML and that inhibiting MSLN shedding is a promising approach to improve CAR T-cell efficacy.</jats:p> </jats:sec>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 27 (20), 5718-5730, 2021-08-11
American Association for Cancer Research (AACR)