Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse
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
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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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 6

Phenotypic changes of the dominant NK cell subsets in the peripheral blood over time.

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Phenotypic changes of the dominant NK cell subsets in the peripheral blo...
NK cell phenotype was compared at screening and day +60 after CIML NK cell infusion using flow cytometry and mass cytometry. (A) Comparison of the CD56dim and CD56bright NK cell subset proportion of total lymphocyte count at screening and day +60. At screening, the median CD56dim NK proportion of lymphocytes was 3.3% (min 1.3%, max 15.2%), while the median CD56bright NK proportion of lymphocytes was 0.7% (min 0.1%, max 1%). On day +60, the median CD56dim proportion of lymphocytes was 32.6% (min 0%, max 50.9%), while the median CD56bright NK proportion of lymphocytes was 2.5% (min 0 %, max 8.4%). (B) tSNE plot comparison of PBMC populations at screening and day +60 time points in representative patient 3. NK cells are in the red circle. (C) Differential expression of mass cytometry markers in the CD3–CD56dim cell subpopulations (Wilcoxon’s rank-sum test, with significance adjusted for multiple comparisons). Screening (n = 6) and day +60 (n = 5). Patient 5 did not have a day +60 sample. (D) Clustering of PBMCs to identify the Ki67+ subpopulation (red squares) of CD3–CD56+ NK cells. CD3–CD56+Ki67+ cells as a proportion of total PBMCs at both screening and day +60. Individual patient values are shown superimposed on the box plots. The median percentage of CD3–CD56+Ki67+ cells at screening and day +60 was 0.075% (min 0%, max 0.09%) and 0.32% (min 0.07%, max 1.15%), respectively. *Differential abundance, with P < 0.05 using Wilcoxon’s rank-sum test.