Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering

Li Li; Vakul Mohanty; Jinzhuang Dou; Yuefan Huang; Pinaki P. Banerjee; Qi Miao; Jens G. Lohr; Tushara Vijaykumar; Julia Frede; Birgit Knoechel; Luis Muniz-Feliciano; Tamara J. Laskowski; Shaoheng Liang; Judy S. Moyes; Vandana Nandivada; Rafet Basar; Mecit Kaplan; May Daher; Enli Liu; Ye Li; Sunil Acharya; Paul Lin; Mayra Shanley; Hind Rafei; David Marin; Stephan Mielke; Richard E. Champlin; Elizabeth J. Shpall; Ken Chen; Katayoun Rezvani

doi:10.1126/sciadv.add6997

Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering

Li Li, Vakul Mohanty, Jinzhuang Dou, Yuefan Huang, Pinaki P. Banerjee, Qi Miao, Jens G. Lohr, Tushara Vijaykumar, Julia Frede, Birgit Knoechel, Luis Muniz-Feliciano, Tamara J. Laskowski, Shaoheng Liang, Judy S. Moyes, Vandana Nandivada, Rafet Basar, Mecit Kaplan, May Daher, Enli Liu, Ye LiSunil Acharya, Paul Lin, Mayra Shanley, Hind Rafei, David Marin, Stephan Mielke, Richard E. Champlin, Elizabeth J. Shpall, Ken Chen, Katayoun Rezvani

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Abstract

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is promising, with early-phase clinical studies showing encouraging responses. However, the transcriptional signatures that control the fate of CAR-NK cells after infusion and factors that influence tumor control remain poorly understood. We performed single-cell RNA sequencing and mass cytometry to study the heterogeneity of CAR-NK cells and their in vivo evolution after adoptive transfer, from the phase of tumor control to relapse. Using a preclinical model of noncurative lymphoma and samples from a responder and a nonresponder patient treated with CAR19/IL-15 NK cells, we observed the emergence of NK cell clusters with distinct patterns of activation, function, and metabolic signature associated with different phases of in vivo evolution and tumor control. Interaction with the highly metabolically active tumor resulted in loss of metabolic fitness in NK cells that could be partly overcome by incorporation of IL-15 in the CAR construct.

Original language	English (US)
Article number	eadd6997
Journal	Science Advances
Volume	9
Issue number	30
DOIs	https://doi.org/10.1126/sciadv.add6997
State	Published - Jul 2023

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Li, L., Mohanty, V., Dou, J., Huang, Y., Banerjee, P. P., Miao, Q., Lohr, J. G., Vijaykumar, T., Frede, J., Knoechel, B., Muniz-Feliciano, L., Laskowski, T. J., Liang, S., Moyes, J. S., Nandivada, V., Basar, R., Kaplan, M., Daher, M., Liu, E., ... Rezvani, K. (2023). Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering. Science Advances, 9(30), Article eadd6997. https://doi.org/10.1126/sciadv.add6997

Li, L , Mohanty, V , Dou, J, Huang, Y, Banerjee, PP, Miao, Q, Lohr, JG, Vijaykumar, T, Frede, J, Knoechel, B, Muniz-Feliciano, L, Laskowski, TJ, Liang, S, Moyes, JS, Nandivada, V, Basar, R, Kaplan, M, Daher, M, Liu, E, Li, Y, Acharya, S , Lin, P , Shanley, M , Rafei, H , Marin, D, Mielke, S, Champlin, RE , Shpall, EJ , Chen, K & Rezvani, K 2023, 'Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering', Science Advances, vol. 9, no. 30, eadd6997. https://doi.org/10.1126/sciadv.add6997

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title = "Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering",

abstract = "Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is promising, with early-phase clinical studies showing encouraging responses. However, the transcriptional signatures that control the fate of CAR-NK cells after infusion and factors that influence tumor control remain poorly understood. We performed single-cell RNA sequencing and mass cytometry to study the heterogeneity of CAR-NK cells and their in vivo evolution after adoptive transfer, from the phase of tumor control to relapse. Using a preclinical model of noncurative lymphoma and samples from a responder and a nonresponder patient treated with CAR19/IL-15 NK cells, we observed the emergence of NK cell clusters with distinct patterns of activation, function, and metabolic signature associated with different phases of in vivo evolution and tumor control. Interaction with the highly metabolically active tumor resulted in loss of metabolic fitness in NK cells that could be partly overcome by incorporation of IL-15 in the CAR construct.",

author = "Li Li and Vakul Mohanty and Jinzhuang Dou and Yuefan Huang and Banerjee, {Pinaki P.} and Qi Miao and Lohr, {Jens G.} and Tushara Vijaykumar and Julia Frede and Birgit Knoechel and Luis Muniz-Feliciano and Laskowski, {Tamara J.} and Shaoheng Liang and Moyes, {Judy S.} and Vandana Nandivada and Rafet Basar and Mecit Kaplan and May Daher and Enli Liu and Ye Li and Sunil Acharya and Paul Lin and Mayra Shanley and Hind Rafei and David Marin and Stephan Mielke and Champlin, {Richard E.} and Shpall, {Elizabeth J.} and Ken Chen and Katayoun Rezvani",

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year = "2023",

month = jul,

doi = "10.1126/sciadv.add6997",

language = "English (US)",

volume = "9",

journal = "Science Advances",

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AU - Banerjee, Pinaki P.

AU - Miao, Qi

AU - Lohr, Jens G.

AU - Vijaykumar, Tushara

AU - Frede, Julia

AU - Knoechel, Birgit

AU - Muniz-Feliciano, Luis

AU - Laskowski, Tamara J.

AU - Liang, Shaoheng

AU - Moyes, Judy S.

AU - Nandivada, Vandana

AU - Basar, Rafet

AU - Kaplan, Mecit

AU - Daher, May

AU - Liu, Enli

AU - Li, Ye

AU - Acharya, Sunil

AU - Lin, Paul

AU - Shanley, Mayra

AU - Rafei, Hind

AU - Marin, David

AU - Mielke, Stephan

AU - Champlin, Richard E.

AU - Shpall, Elizabeth J.

AU - Chen, Ken

AU - Rezvani, Katayoun

PY - 2023/7

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AB - Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is promising, with early-phase clinical studies showing encouraging responses. However, the transcriptional signatures that control the fate of CAR-NK cells after infusion and factors that influence tumor control remain poorly understood. We performed single-cell RNA sequencing and mass cytometry to study the heterogeneity of CAR-NK cells and their in vivo evolution after adoptive transfer, from the phase of tumor control to relapse. Using a preclinical model of noncurative lymphoma and samples from a responder and a nonresponder patient treated with CAR19/IL-15 NK cells, we observed the emergence of NK cell clusters with distinct patterns of activation, function, and metabolic signature associated with different phases of in vivo evolution and tumor control. Interaction with the highly metabolically active tumor resulted in loss of metabolic fitness in NK cells that could be partly overcome by incorporation of IL-15 in the CAR construct.

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Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering

Abstract

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