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 4

Distribution of adaptive and nonadaptive CD56dim NK cell populations and markers in the CMV+ (n = 3) and CMV– (n = 2) groups.

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Distribution of adaptive and nonadaptive CD56dim NK cell populations and...
(A) UMAP of PBMC subpopulations identified by mass cytometric analysis showing both CMV+ (light green) and CMV– (red) cells on both day +7 and day +28. (B) Distribution of adaptive and nonadaptive CD56dim NK cells in the CMV– (green) and CMV+ group (orange) on day +7 and day +28 after CIML NK cell infusion. (C) Differential expression of markers on the nonadaptive CD56dim NK cell subpopulations on day +28 after CIML NK cell infusion shows no differences in this subpopulation between CMV+ and CMV– groups. *P < 0.05 by Wilcoxon’s rank-sum test, with significance adjusted for multiple comparisons (43). (D) UMAP of PBMC subpopulations in CMV+ and CMV– patients evaluated with scRNA-seq on day +28 after CIML NK cell infusion. The adaptive Dim1, Dim2, Dim5, and Dim6 subpopulations are expanded predominantly in the CMV+ group, while the Dim3 and Dim4 subpopulations are comparable between groups. (E) Volcano plot to show the most differentially expressed genes in the adaptive CD56dim NK cell clusters between CMV+ and CMV– groups (P-value cutoff = 10 × 10–32, fold change cutoff = 0.1). The MAST test was used to determine differentially expressed markers between the 2 groups (log[fold change] threshold = 0.25). (F) Dot plot showing genes defining the individual clusters identified in the CMV+ and CMV– patient groups on day +28 after infusion. Subsets of genes corresponding to CD56bright, adaptive CD56dim, and nonadaptive CD56dimCD16+ NK cells are indicated.