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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI193053

Engineered NKG2C+ CD8+ TKLR cells exhibit effective antitumor control in mice while mitigating cytokine release syndrome

Kyle B. Lupo,1 M. Kazim Panjwani,1 Aya G. Halawi,1 Sanam Shahid,2 Rosa Sottile,1 Clara Lawry,1 Gabryelle Kolk,1 Theodota Kontopoulos,1 Anthony F Daniyan,3 Smita S. Chandran,1 Christopher A. Klebanoff,1 and Katharine C. Hsu1

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Lupo, K. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Panjwani, M. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Halawi, A. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Shahid, S. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Sottile, R. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Lawry, C. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Kolk, G. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Kontopoulos, T. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Daniyan, A. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Chandran, S. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Klebanoff, C. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Hsu, K. in: PubMed | Google Scholar

Published October 21, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI193053.
Copyright © 2026, Lupo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 21, 2026 - Version history
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Abstract

Engineered T and NK cell therapies have widely been used to treat hematologic malignancies and solid tumors, with promising clinical results. Current chimeric antigen receptor (CAR) T cell therapeutics are, however, associated with treatment-related adverse events such as cytokine release syndrome (CRS) and are prone to immunologic exhaustion. CAR-NK therapeutics, while not associated with CRS, have limited in vivo persistence. We now demonstrate that a population of NK-like TCRαβ+ CD8 T cells (TKLR), identified and expanded ex vivo through its expression of the activating receptor NKG2C, can be transduced to express a second-generation CD19 CAR (1928z). These CAR+ TKLR demonstrates superior tumor clearance and longer persistence compared to 1928z CAR+ conventional CD8 T cells (TConv) and 1928z CAR+ NK cells in mouse xenograft models. Moreover, CAR-modified TKLR had decreased expression of PD-1, TIM-3, and LAG-3 and elicited significantly reduced CRS compared to CAR+ CD8 TConv in mouse xenograft models. Similarly, NKG2C+ TKLR engineered with a TCR targeting the NY-ESO-1 antigen exhibited robust tumor control compared to TCR-engineered CD8 TConv in a mouse xenograft model. These data establish NKG2C+ TKLR as a promising platform for cell engineering, and offer a safer, more durable alternative to conventional CAR-T and CAR-NK therapies.

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  • Version 1 (October 21, 2026): In-Press Preview
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