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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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 3

Evaluation of subpopulations of NK cells present in the infusion product over time.

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Evaluation of subpopulations of NK cells present in the infusion product...
(A) Median proportion of total PBMCs that were CD56+CD3– at the indicated time points. Days after infusion of the CIML NK product are indicated above the time point labels. (B) UMAP of NK cell clusters defined with single-cell RNA sequencing at day +28 compared to the infusion product for all patients whose CIML NK cells expanded. The CD56dim NK cell subpopulations that persist include Dim1, Dim2, CD56bright, and adaptive NK cells. (C) Identification of defined NK cell subpopulations based on transcriptional profiling reveals the expansion of several CD56dim subpopulations and adaptive CD56dim NK cell populations. The heatmap shows the top 5 differentially expressed genes in each NK cell cluster when compared with other clusters using Wilcoxon’s rank-sum test (log[fold change] threshold = 0.25). (D) Volcano plot showing the top differentially expressed genes in all CD56dim clusters between infusion and day +28; fold change cutoff = 0.5, P-value cutoff = 10 × 10–32. Differential gene expression was determined using the nonparametric Wilcoxon’s rank-sum test. (E) Violin plot to show the expression of select genes within the CD56dim, CD56bright, and adaptive CD56dim NK populations at infusion (red) and day +28 (green) time points. Shown are the most differentially expressed markers as well as genes associated with NK cell activation. (F) Evaluation of NK cell subpopulations over time as a proportion of total NK cells in each of the clinical trial patients treated with CIML NK cell therapy. Key subpopulations include adaptive NK cells (CD56+CD3–CD57+KIR+NKG2C+FcεRI–), CD56bright NK cells (CD56hiCD3–NKG2A+IL-7R+), CD56dimNKG2A+ NK cells, and CD56dimKi67+ NK cells, among others. The sample time points for each patient are labeled. INF, at time of infusion.