Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse
Roman M. Shapiro, … , Jerome Ritz, Rizwan Romee
Roman M. Shapiro, … , Jerome Ritz, Rizwan Romee
Published March 29, 2022
Citation Information: J Clin Invest. 2022;132(11):e154334. https://doi.org/10.1172/JCI154334.
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Clinical Research and Public Health

Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse

Abstract

Background Responses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell–based therapy is a promising modality to treat post-HCT relapse.Methods We initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion.Results In the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires.Conclusion Given their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.Trial Registration ClinicalTrials.gov NCT04024761.Funding Dunkin’ Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.

Authors

Roman M. Shapiro, Grace C. Birch, Guangan Hu, Juliana Vergara Cadavid, Sarah Nikiforow, Joanna Baginska, Alaa K. Ali, Mubin Tarannum, Michal Sheffer, Yasmin Z. Abdulhamid, Benedetta Rambaldi, Yohei Arihara, Carol Reynolds, Max S. Halpern, Scott J. Rodig, Nicole Cullen, Jacquelyn O. Wolff, Kathleen L. Pfaff, Andrew A. Lane, R. Coleman Lindsley, Corey S. Cutler, Joseph H. Antin, Vincent T. Ho, John Koreth, Mahasweta Gooptu, Haesook T. Kim, Karl-Johan Malmberg, Catherine J. Wu, Jianzhu Chen, Robert J. Soiffer, Jerome Ritz, Rizwan Romee

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Figure 2

Rapid expansion of NK cells follows infusion of CIML NK product into the patients.

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Rapid expansion of NK cells follows infusion of CIML NK product into the...
(A) Mean NK cell counts/μL of peripheral blood determined from the lymphocyte count. (B) Flow cytometry was used to evaluate NK cells in the peripheral blood as a proportion of total lymphocytes. Data presented are CD56+CD3– cells as a percentage of total lymphocytes, mean ± SD. Right: Tregs (CD3+CD4+CD25+CD127–) cells as a percentage of total lymphocytes, mean ± SD. The value for each patient is shown with a colored dot, and the coloring scheme corresponds to that in panel A. *P < 0.05 by Mann-Whitney U test, with significance adjusted by Holm’s method for multiple comparisons. (C) Flow cytometry–based evaluation of key markers distinguishing the CD56dim NK cell population from the CD56bright NK cell population. There was no significant difference in expression of markers between time points as determined by the Mann-Whitney U test. (D) Differential expression analysis of mass cytometry markers in the predominant CD56dim clusters between day 0 (infusion product) and day +28 after infusion. Markers labeled in red are differentially expressed (Wilcoxon’s signed-rank test, P < 0.05). (E) Functional characterization of the expanded NK cell compartment using both cytokine stimulation and coculture with K562 target cells at an E:T ratio of 5:1. The y axis shows percentage expression of the indicated marker relative to the corresponding unstimulated control, and the dashed line represents the same functional assays applied to healthy donor control PBMCs. In B, C, and E, the screening time point (Scr) refers to endogenous patient NK cells prior to infusion. *P < 0.05 by Mann-Whitney U test. (F) Measurement of plasma cytokines following CIML NK cell infusion. The x axis of each plot shows days relative to CIML NK cell infusion (day 0).