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. Author manuscript; available in PMC: 2026 Mar 21.
Published in final edited form as: Transplant Cell Ther. 2023 Nov 30;30(2):203.e1–203.e9. doi: 10.1016/j.jtct.2023.11.022

EX VIVO-EXPANDED CORD BLOOD NK CELLS COMBINED WITH RITUXIMAB AND HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS SCT FOR B-NHL

Yago Nieto 1, Pinaki Banerjee 1, Indresh Kaur 1, Kun Hee Kim 2, Dexing Fang 1, Peter F Thall 3, Lori Griffin 1, Melissa Barnett 1, Rafet Basar 1, Chitra Hosing 1, Jeremy Ramdial 1, Samer Srour 1, May Daher 1, David Marin 1, Xianli Jiang 2, Ken Chen 2, Richard Champlin 1, Elizabeth J Shpall 1, Katayoun Rezvani 1
PMCID: PMC13003571  NIHMSID: NIHMS2136673  PMID: 38042257

Abstract

BACKGROUND:

Relapse is the major cause of failure of high-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) for B-cell non-Hodgkin lymphomas (B-NHL). Improvement venues include its combination with effective immunotherapies.

OBJETIVES:

We hypothesized that the combination of rituximab/HDC/ASCT with expanded cord blood (CB)-derived NK cells is safe and active in B-NHL.

STUDY DESIGN:

B-NHL patients, ages 15-70 and appropriate ASCT candidates, were eligible. The CB units were selected without considering HLA match with the recipient. The CB NK cells were expanded from day −19 to −5. Treatment included rituximab (days −13 and −7), BEAM (carmustine/etoposide/cytarabine/melphalan, d-13 to −7), lenalidomide (d-7 to −2), CB NK infusion (108/kg, day −5), and ASCT (d0). The primary endpoint was 30-day treatment-related mortality (TRM). Secondary endpoints included relapse-free (RFS), overall survival (OS), and persistence of CB NK cells.

RESULTS:

We enrolled 20 patients. CB NK cells were expanded a median 1,552-fold with >98% purity and >96% viability. We saw no adverse events attributable to the CB NK cells and 0% 30-day TRM. At median follow-up of 47 months, the RFS/OS rates are 53%/74%. CB NK cells were detectable in blood for 2 weeks, independently of their HLA mismatch. CD16 expression in donor NK cells correlated favorably with outcome. Further, homozygosity for the high-affinity CD16 variant (158 V/V) in CB, but not recipient, NK cells, correlated with better outcomes.

CONCLUSIONS:

The combination of expanded and highly purified CB-derived NK cells with HDC/ASCT for B-NHL is safe. CD16 expression in donor NK cells, particularly if homozygous for the high-affinity CD16 variant, correlated with better outcomes.

INTRODUCTION

Following decades of treating patients with relapsed B-cell non-Hodgkin lymphomas (NHL) with high-dose chemotherapy (HDC) and autologous stem-cell transplant (ASCT), tumor relapse remains the major cause of treatment failure.1 While autologous CAR-T cells have recently shown improved outcomes compared to HDC/ASCT in refractory or poor-risk relapsed DLBCL,2, 3 more than 50% of patients still relapse after CAR-T and most of them face a dismal prognosis.4, 5 HDC/ASCT could still be useful for these patients if its antitumor efficacy were increased. Promising venues of improvement include the combination of HDC with effective adoptive immune therapies.

Natural killer (NK) cells are part of the innate immune system and have been implicated in tumor immunity and defense, without requirement of prior exposure or sensitization to kill a specific target.6 Robust NK cell reconstitution has been associated with improved outcomes for NHL after HDC/ASCT.7,8,9 Unfortunately, autologous NK cells from patients with lymphoma are dysfunctional, due to, among other causes, an unfavorable balance between activating and inhibitory receptors.10,11,12 While immunomodulatory drugs, such as lenalidomide,13,14,15,16 or cytokines, such as IL-12, 17 may augment NK cell function after ASCT, clinical experience has shown that this is not sufficient to prevent disease progression. Therefore, successful NK immunotherapy activity against lymphoma may require an allogeneic source.

The clinical safety of peripheral blood-derived allogeneic NK cell infusions has been demonstrated.18,19 This requires collection of peripheral blood from a normal donor to generate NK cells, which can be logistically cumbersome. To minimize obstacles to collection, our group’s interest has focused on NK cells derived from cryopreserved umbilical cord blood (CB), a known source of hematopoietic progenitor cells and an “off-the-shelf” product. We developed a good manufacturing practice (GMP)-grade method of NK cell expansion from thawed CB mononuclear cells based on artificial antigen-presenting cells, which yields a >1,000-fold expansion of NK cells with in vitro and in vivo antitumor activity.20 Using this technology, we saw good tolerability of expanded CB-NK cells (up to 108 NK cells/kg) combined with high-dose melphalan and ASCT in patients with myeloma.21

Preclinical data indicate that ex vivo activated and expanded CB-NK cells can mediate dose-dependent cytotoxicity against B-cell lymphoma lines, which is enhanced in the presence of lenalidomide.22 Those preclinical results and our clinical experience in myeloma prompted us to study of this novel cellular therapy in patients with B-cell lymphoma receiving HDC/ASCT. Concomitant with CB-NK cells, patients received rituximab to enhance NK activity through antibody-dependent cellular cytotoxicity (ADCC) and lenalidomide to support NK proliferation and effector function.

PATIENTS AND METHODS

Patient Population

The study protocol was approved by the Clinical Research Committee and Institutional Review Board of MD Anderson Cancer Center and registered at NCI.gov (NCT03019640). Patients provided written informed consent prior to enrollment. Eligibility included age 15-70 and B-cell lymphoma candidate for ASCT, including primary refractory or relapsed DLBCL in response to salvage treatment (excluding primary CNS lymphoma), primary refractory or relapsed follicular lymphoma or other indolent B-cell histology in response to salvage treatment, and chemosensitive mantle-cell lymphoma after first or later line of treatment, and having completed apheresis of ≥2 million CD34+ cells/kg. Additional eligibility criteria included adequate renal (creatinine clearance ≥50 ml/min), hepatic (SGOT/SGPT/bilirubin ≤3x upper normal limit, pulmonary (FEV1/FVC/DLCOc ≥50%) and cardiac function (left ventricular ejection fraction ≥40%), performance status 0-1, no prior whole brain irradiation or any radiation within one month of enrollment, no active hepatitis B, and no chronic hepatitis C causing cirrhosis/stage 3-4 fibrosis. There was no requirement for any degree of HLA matching between the cord blood unit and the patient.

Phenotyping and tracking of donor-derived, CB-NK cells

To determine the persistence of donor-derived CB-NK cells in the peripheral blood, we used a flow-chimerism assay that detected the mismatch in the HLA genotype between the CB-NK cells and the recipient using fluorochrome-conjugated antibodies against HLA antigens. Flow cytometry was performed on a BD LSRFortessa X-20 instrument, and data were analyzed with the Kaluza software, version 2.1 (Beckman Coulter). The phenotype of the circulating NK cells was evaluated using antibodies against CD45 (BD Biosciences: Clone HI30) PE-Cy5; CD3 (BD Biosciences: Clone UCHT1) APC-Cy7, NKG2C (R&D Systems Clone134591) AF488; NKp44 (BioLegend. Clone P44-8) PerCP; NKG2D (BioLegend. Clone 1D11) BV421; NKG2A (BioLegend. Clone S19004C) PE-Cy7; NKp30 (BD Biosciences. Clone p30-15) BUV395; CD16 (BioLegend. Clone 3G8) BV650; NKp46 (BioLegend. Clone 9E2) BV711; CD57 (BD Biosciences. Clone NK-1) PE-CF594; Live dead dye (TonBo BioScience) UV450 by multiparametric flow cytometry as previously described.23

NK-cells were identified by gating on CD56+CD3− cell population from each sample and transformed raw expressions of each marker using hyperbolic arcsine with a cofactor of 150. We applied cutoffs for expressions at each marker to remove background signal. Each sample was downsized to 5,000 cells per sample for analysis. We used Phenograph clustering in Cytotree 24, 25 in R to identify subpopulations in the data, with the number of nearest neighbors set at 45. We applied t-SNE to visualize high-dimensional flow cytometry data to 2-dimensional plot. For each cluster, means of transformed marker expression were used to profile expression pattern. Subpopulations with similar marker expression profile were merged into a metacluster when localized nearby to each other on t-SNE. Data from a patient with unknown status was only used to define metaclusters and their expression profile and excluded from further analysis.

FCGRIIIA genotyping

Genomic DNA was extracted from cord blood units using the QIAamp DNA Mini isolation kit (Qiagen, Venlo, The Netherlands) according to manufacturer’s instruction. To determine FCGRIIIA 158 polymorphism (SNP ID: rs396991, Assay ID: C_25815666_10), predesigned TaqMan MGB probe pairs that detect each allele were purchased from Thermo Fisher Scientific (Waltham, MA), along with the TaqMan® genotyping master mix (catalog # 4371353).26,27 Following the manufacturer’s instructions, SNP genotyping PCR was performed using the AB7500 Fast Real PCR system. The 158V/F polymorphism was determined by system software analysis and manual calculation based on the ratio of allele 1 to allele 2.

Treatment Plan (Table 1).

Table 1.

Treatment Schema.

Day
No later than −19 Begin NK cell production
−13 Rituximab 375 mg/m2 IV
−12 Carmustine 300 mg/m2 IV
−11 to −8 Etoposide 200 mg/m2 IV BID
Cytarabine 200 mg/m2 IV BID
−7 Melphalan 140 mg/m2
Lenalidomide, 10 mg PO
Rituximab 375 mg/m2 mg/m2 IV
−6 to −2 Lenalidomide, 10 mg PO
−5 CB NK cell Infusion (up to 108/kg)
0 Autologous PBPC infusion
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The NK cells used in the treatment of each patient were derived from an individual unit of frozen CB. The CB-derived NK cells cells were expanded in liquid cultures using APC feeder cells at the MD Anderson Cancer Center GMP Laboratory as previously described,15 starting no less than 14 days (day −19) prior to their infusion on day −5. Rituximab was administered at 375 mg/m2 IV on day −13. From day −12 to day −7 patients received BEAM (carmustine/etoposide/cytarabine/melphalan). On day −7 patients received a second dose of rituximab at 375 mg/m2. Lenalidomide was administered at 10 mg PO daily from day −7 to −2. Steroids were contraindicated from day −8 to +3.

On day −5 the expanded CB NK cells (108/Kg) were infused with diphenhydramine and acetaminophen premedication. The NK release criteria included >80%CD16+ CD56+cells, undetectable APCs (CD32+ CD19+ CD56−) in the viable population, absence of microorganisms by Gram stain, no evidence of contamination by visual inspection, CD3+ cells < 2 x 105/kg, endotoxin assay < 5 EU/Kg, and TNC cell viability ≥70%.

The autologous PBPC were infused on day 0. G-CSF was administered subcutaneously at 5 mcg/kg/day from day +5 until neutrophil engraftment. Departmental guidelines for post-transplant antiemetics, antimicrobials and blood product transfusions were followed.

Disease assessments with PET or CT scans, and BM exam if indicated, were performed at 1, 3 and 6 months post-HDC, and every 6 months thereafter. PET scans were interpreted using the Deauville five-point scale.28

To determine persistence of CB-derived NK cells in the recipient, serial peripheral blood samples were collected on day −4, day 0 (before infusion of PBPC), day + 7 and weekly thereafter, until negative results are obtained. As described above, we used a flow-chimerism assay based on the mismatch in the HLA genotype between the CB-NK cells and the recipient.

Statistical design

The primary outcome for safety monitoring was transplant related mortality within 30 days (TRM-30), with a TRM-30 probability of 0.10 considered unacceptably high. The method of Thall and Sung was used for safety monitoring.29 Unadjusted RFS and OS were estimated by the method of Kaplan and Meier.30

RESULTS

We enrolled 20 patients between 12/2017 and 07/2020. This treatment was their first SCT or adoptive cellular immunotherapy. Their median age was 60 (range, 33-70); 17 patients had diffuse large B-cell lymphoma (DLBCL), 2 had mantle-cell lymphoma (MCL) and 1 follicular lymphoma (Table 2). One patient, with rapidly progressive disease after enrollment, was not treated on study. Most of the 19 treated patients had chemosensitive relapsed disease.

Table 2.

Patient population.

Age (median, range) 60 (33-70)
Gender: Male / female 14/5
Diagnosis Diffuse large B-cell lymphoma
• Double hit
• sIPI: Median (range)		 16
• 5
• 3 (0-5)
Mantle cell lymphoma 2
Follicular lymphoma 1
Disease status Frontline 2 (MCL)
Primary refractory 4
Relapsed 13
Interval initial diagnosis – enrollment on study (months) 18 (5-111)
Duration first CR (when applicable) (months) 6 (0-100)
No. prior lines of therapy: Median (range) 2 (1-4)
PET response at ASCT: CR / PR / PD 15 / 3/ 1
HLA matching of CB
• 1/6 match at DR
• 1/6 match at B
• 1/6 match at A
• 2/6 match at B, DR		 •9
• 6
• 3
• 1
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sIPI: Secondary International Prognostic Index.

The CB NK cells they received were highly mismatched (1/6 match in 18 patients and 2/6 match in 1 patient). CB NK cells expanded a median 1,552-fold (range, 317-4,767). The infused NK product was highly purified, with a CD3−CD16+CD56+ phenotype in a median 98.91% (range, 97.64-99.54%) of the cells, and a median 96.5% (92-98%) total viability. There were no adverse events attributable to the CB NK, including infusion-related reactions, cytokine release syndrome, neurotoxicity or GVHD. The observed side-effect profile of mucositis (8 cases of grade 2), diarrhea (10 cases of grade 2) and uncomplicated neutropenic fever in 14 patients were within the expected toxicity profile of HDC/BEAM. Neutrophils and platelets engrafted promptly in all patients at median day 10 (9-13) and 13 (9-18), respectively. There were no cases of delayed cytopenias. Post-ASCT infections included 1 case each of pneumonia and COVID-19. The 30-day and 1-year TRM were both 0% We saw no cases of secondary MDS/AML.

At median follow-up of 47 months (37-63), 10 patients are alive in remission (53% EFS) and 14 patients are alive (74% OS) (Figure 1).

Figure 1.

Figure 1.

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Event-free survival (EFS) and overall survival (OS) Kaplan-Meier curves of the study population.

Multiparameter flow cytometry analysis of NK cells (Figure 2).

Figure 2.

Figure 2.

Figure 2.

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Multiparameter flow cytometry analysis of NK cells. Fig 2-A: Gating strategy to identify donor and patient NK cells. Fig. 2-B: Expansion of cord blood- derived donor NK cells. The top panel dot plot shows persistence of donor NK cell by donor-specific HLA staining (red), which is absent on recipient (black) at two different time points on both a “remitter” and a “non-remitter”. The bottom panel shows the histograms for donor NK cell (red) and recipient NK cell (black) from the top panel, showing the percentages of CD16+ NK cells. Fig. 2-C: Bar graphs of the expansion of cord blood-derived NK cells in “remitters” (brown bars) and “non-remitters” (gray bars). Fig. 2-D: Percentages of donor NK cells, combining “remitters” and “non-remitters”, from four different time points.

We performed flow cytometry in 42 serial samples from 12 patients in two subgroups: 19 samples from 6 patients who remained in remission (“remitters”) and 23 samples from 6 patients whose lymphoma relapsed at a median of 6 (2-26 months) after ASCT (“non-remitters”). We observed a robust expansion of CD16+ CD56+ CB NK cells in all patients shortly after treatment (Fig.2). Within the first ten days after infusion, CB NK cells expanded rapidly and comprised most of the NK population (87% to 99% in all samples). Subsequently CB NK cells declined in both “remitters” and “non-remitters”, and became nearly absent by the end of the second week. Of note, persistence of CB NK cells was similar between “remitters” and “non-remitters” and it was not affected by the degree of HLA mismatch with the recipient. NK cells from both subgroups had different phenotype, with “remitters” exhibiting an increase in activation markers, most notably CD16, in the first month post ASCT (Fig. 3). “Remitters” and “non-remitters” showed differing trends in the proportion of their total CD16+ NK cells over time. Specifically, “remitters” experienced a rapid expansion of the CD16+ subset shortly after infusion, with a 6.7-fold increase between days +10 and +20, followed by a subsequent decline. In contrast, the CD16+ subset decreased rapidly in the first 3 weeks in “non-remitters”. The HLA mismatch between the infused CB-NK cell product and the recipient allowed us to study the contribution of the donor vs. the recipient to the CD16+ NK cell pool. Among “remitters”, the majority of the CD16+ population in the first 10 days was CB derived, accounting for 83.3% of the total CD16+ subset. Between days +10 and +20 the recipients’ CD16+ cells increased from 5% to 54%, and represented the entirety of the CD16+ NK-cells after day +20. In contrast, “non-remitters” exhibited a delayed recovery in both donor and recipient CD16+ NK-cells, with reconstitution of recipient CD16+ NK cells observed only after 20 days and comprising approximately only 14% of all cells.

Figure 3.

Figure 3.

Figure 3.

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Phenotype analysis of NK cells. Fig. 3-A: Phenograph analysis of all samples overlaid on a t-distributed stochastic neighbor embedding (tSNE) map, identifying 26 distinct NK-cell metaclusters. Fig. 3-B: Heatmap summarizing the expression of different markers in each metacluster. Fig. 3-C: tSNE map of samples from “remitters” (top) and “non-remitters” (bottom) in each timeframe. Fig. 3-D: Analysis of CD16+ NK-cells depicting changes in the ratio of each metacluster in samples at each timeframe. Fig. 3-E: Distribution of CD16+ NK-cells in the first (day 0 to +10) and second (day +10 to +20) timeframe after infusion. Fig. 3-F: Expression of CD16 in host NK cells: Percentages of CD16+ recipient NK cells in “remitters” (green) and “non-remitters” (pink) from 3 different time points. Each dot represents a patient and bar is the mean, error bars represent SEM. The increase of CD16+ NK cells in remitters is not statistically significant (ns).

FCGR3A-VV genotype is a predictor of outcomes

We genotyped the FCGR3A gene that encodes CD16 in donor-derived and recipient NK cells from 11 patients. In this small sample we saw that 158 V/V homozygosity (FCGR3A-VV), which results in high affinity binding of CD16 to Fc-γ in antibodies, correlated with better outcomes when present in the CB NK cells (P=0.01), but not in patient NK cells (P=0.9) (Figure 4).

Figure 4.

Figure 4.

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CD16 genotyping of cord blood-derived (Fig. 4-A) and patient-derived (Fig. 4-B) NK cells.

DISCUSSION

Our study shows that the combination of expanded CB-derived NK cells with HDC and ASCT in B-NHL patients is safe. Concomitant with CB-NK cells, patients received rituximab to enhance NK activity through antibody-dependent cellular cytotoxicity (ADCC) and lenalidomide to support NK proliferation and effector function. As expected in the absence of cytokine support, CB NK cells were detected in the blood for around 2 weeks. Importantly for its “off-the-shelf” availability, their degree of HLA disparity with the patient had no impact on their persistence or in any clinical parameter of toxicity or efficacy.

Expression of CD16, the Fc-γ receptor responsible for binding to IgG complexes and mediating ADCC, on NK cells in the first two weeks post-infusion correlated with better outcomes. Furthermore, FCGRIIIA genotyping in CB NK and patient NK cells showed that the high-affinity V/V variant at the amino acid position 158 in CB NK cells, but not in patient NK cells, was a predictor of favorable outcomes, which is a novel observation in NK cell adoptive immunotherapy. Homozygosity for 158 V/V results in higher CD16 expression and had been previously shown to increase binding to monoclonal antibodies, including rituximab.31, 32 While our novel observations are preliminary due to the small sample size, they suggest a major role for ADCC by the CB NK.

In recent years, several groups including ours have further developed allogeneic NK cells for B-NHL by genetic modification to express a chimeric antigen receptor (CAR) targeting a B-cell antigen. We previously reported high activity and safety of CB-derived CD19.CAR NK cells given after lymphodepleting chemotherapy in 11 patients with relapsed B-NHL or chronic lymphocytic leukemia.33 In contrast to nontransduced allogeneic NK cells, NK cells that are genetically modified to express both a CAR and IL-15, a cytokine that plays an important role in NK cell persistence and proliferation, persist for much longer periods. Indeed, in our clinical trial with CB-derived CAR19/IL-15 in B cell malignancies, we could detect the cells for a year or longer post infusion.28 Similarly, Cichocki et al. generated NK cells from induced pluripotent stem cells transduced with a CD19.CAR and high-affinity non-cleavable CD16,34 which are currently undergoing clinical testing. Our data also suggest the benefit of banking CD16 158 V/V specific NK cells for future therapy.

Strengths of our study include the novelty of combining HDC with expanded CB NK cells in a homogeneous fashion and the correlative studies that supported our initial mechanistic hypothesis. Its weaknesses include its small sample size and the heterogeneity of B-NHL diagnoses, although most patients had high-risk relapsed DLBCL with a short median CR1 of 6 months. Further, the addition of HDC makes it difficult to establish the relative effect of the CB NK cells in patient outcomes.

In conclusion, the combination of expanded and highly purified CB NK with HDC/ASCT for B-NHL is safe. Further development of this strategy, eg., by combining CB-derived CAR NK cells with HDC, is warranted.

HIGHLIGHTS:

  • We administered expanded CB NK cells with rituximab/HDC/ASCT to B-NHL patients

  • No toxicities were seen after infusion of highly HLA mismatched CB-derived NK cells

  • CD16 expression in donor NK cells correlated with better outcomes

    Homozygosity for the high-affinity CD16 variant increased the CB NK cell activity

CONFLICTS OF INTEREST:

Yago Nieto: Research grants from Astra Zeneca, Novartis, Secura Bio and Affimed.

Elizabeth Shpall: License agreements from Takeda, Affimed and Syena. Consulting fees from Synthego Corporation, Bayer, ASC Therapeutics, Novartis, Mangenta, Cimeio Therapeutics AG, NY Blood Center, Adaptimmune, Navan, Celaid Therapeutics, Zelluna Immunotherapy, FibrioBiologics and Axio.

Katayoun Rezvani: License agreements from Takeda and Affimed. Scientific Advisory Board for GemoAb, AvengeBio, Virogin, GSK, Bayer, and Caribou.

The rest of the authors have no COI disclosures.

Supported by the MD Anderson Lymphoma Moonshot.

Footnotes

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REFERENCES

  • 1.Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010;28:4184–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med 2022;386:640–654. [DOI] [PubMed] [Google Scholar]
  • 3.Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood 2023;141:1675–1684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Chong EA, Rulela M, Schuster SJ. Five-year outcomes for refractory B-cell lymphomas with CAR T-cell therapy. N Engl J Med 2021;384:673–674. [DOI] [PubMed] [Google Scholar]
  • 5.Chow VA, Gopal AK, Maloney DG, et al. Outcomes of patients with large B-cell lymphomas and progressive disease following CD19-specific CAR T-cell therapy. Am J Hematol 2019;94:E209–E213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Guillerey C, Smyth MJ: NK Cells and Cancer Immunoediting. Curr Top Microbiol Immunol 2016;395:115–45. [DOI] [PubMed] [Google Scholar]
  • 7.Leung W, Handgretinger R, Lyengar R, et al. Inhibitory KIR-HLA receptor-ligand mismatch in autologous haematopoietic stem cell transplantation for solid tumour and lymphoma. Br J Cancer, 97 (2007), pp. 539– 542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Porrata LF, Inwards DJ, et al. Interleukin-15 Affects Patient Survival through Natural Killer Cell Recovery after Autologous Hematopoietic Stem Cell Transplantation for Non-Hodgkin Lymphomas. Clinical and Developmental Immunology, vol. 2010, Article ID 914945, 13 pages, 2010. doi: 10.1155/2010/914945 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Porrata LF, Inwards DJ, Ansell SM, et al. Early lymphocyte recovery predicts superior survival after autologous stem cell transplantation in non-Hodgkin lymphoma: a prospective study. Biol Blood Marrow Transplant 2008; 14:807–816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Roma S , Camisaschi C, Mancuso P. Dampening of cytotoxic innate lymphoid cells: A new tumour immune escape mechanism in B cell non-Hodgkin’s lymphoma Cell Immunol 202; :382:104615. [DOI] [PubMed] [Google Scholar]
  • 11.Reiners KS, Kessler J, Sauer M, et al. Rescue of impaired NK cell activity in hodgkin lymphoma with bispecific antibodies in vitro and in patients. Mol Ther 2013;21:895–903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Kobayashi T, Lam PY, Jiang H. Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment. Blood 2020;136:3004–3017. [DOI] [PubMed] [Google Scholar]
  • 13.Lagrue K, Carisey A, Morgan DJ, Chopra R, Davis DM. Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds. Blood 2015;126:50–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Zhu D, Corral LG, Fleming YW, Stein B. Immunomodulatory drugs Revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother 2008;57:1849–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 2005;11:5984–92. [DOI] [PubMed] [Google Scholar]
  • 16.Vo DN, Alexia C, Allende-Vega N, Morschhauser F, Houot R, Menard C, Tarte K, Cartron G, Villalba M. NK cell activation and recovery of NK cell subsets in lymphoma patients after obinutuzumab and lenalidomide treatment. Oncoimmunology 2017;7(4):e1409322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Robertson MJ1, Pelloso D, Abonour R, et al. Interleukin 12 immunotherapy after autologous stem cell transplantation for hematological malignancies. Clin Cancer Res 2002;8:3383–93. [PubMed] [Google Scholar]
  • 18.Shi J, Tricot G, Szmania S, et al. : Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br J Haematol 143:641–53, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Szmania S, Lapteva N, Garg T, et al. : Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. J Immunother 38:24–36, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Shah N, Martin-Antonio B, Yang H, et al. : Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity. PLoS One 8:e76781, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Shah N, Li L, Kaur I, et al. Infusion of Ex Vivo Expanded Allogeneic Cord Blood-Derived Natural Killer Cells in Combination with Autologous Stem Cell Transplantation for Multiple Myeloma: Results of a Phase I Study. Blood 2015; 126:929a.26294715 [Google Scholar]
  • 22.Sun B, Shah B, Fiskus W, et al. Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood 2015;126(13):1565–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.De Lima M, St John LS, Wieder ED, et al. : Double-chimaerism after transplantation of two human leucocyte antigen mismatched, unrelated cord blood units. Br J Haematol 119:773–6, 2002. [DOI] [PubMed] [Google Scholar]
  • 24.Levine JH, Simonds EF, Bendall SC, et al. Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis. Cell 2015; 162:184–197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Dai Y, Xu A, Li J, et al. CytoTree: an R/Bioconductor package for analysis and visualization of flow and mass cytometry data. BMC Bioinformatics 2021;22:138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Sondermann P, Huber R, Oosthuizen V, Oosthuizen V, Jacob U: The 3.2-A crystal structure of the human IgG1 Fc fragment-Fc gammaRIII complex. Nature 2000, 406(6793):267–273. [DOI] [PubMed] [Google Scholar]
  • 27.Radaev S, Motyka S, Fridman WH, Sautes-Fridman C, Sun PD: The structure of a human type III Fcgamma receptor in complex with Fc. J Biol Chem 2001, 276(19):16469–16477. [DOI] [PubMed] [Google Scholar]
  • 28.Meignan M, Gallamini A, Itti E, Barrington S, Haioun C, Polliack A. Report on the Third International Workshop on Interim Positron Emission Tomography in Lymphoma held in Menton, France, 26–27 September 2011 and Menton 2011 consensus. Leuk Lymphoma 2012 53):1876–81. [DOI] [PubMed] [Google Scholar]
  • 29.Thall PF, Sung H-G. Some extensions and applications of a Bayesian strategy for monitoring multiple outcomes in clinical trials. Statistics in Medicine, 17:1563–1580, 1998. [DOI] [PubMed] [Google Scholar]
  • 30.Kaplan EL and Meier P: Nonparametric estimator from incomplete observations. J. American Statistical Association 53:457–81, 1958. [Google Scholar]
  • 31.Hatjiharissi E, Xu L, Santos D, et al. Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism. Blood 2007:110:2561–2564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Veeramani S, Siao-Yi Wang S-Y, Dahle C, et al. Rituximab infusion induces NK activation in lymphoma patients with the high-affinity CD16 polymorphism. Blood 2011;118:3347–3349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med 2020:382:545–553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Cichocki F, Goodridge JP, Bjordhal R, et al. Dual antigen-targeted off-the-shelf NK cells show durable response and prevent antigen escape in lymphoma and leukemia Blood 2022;140:2451–2462. [DOI] [PMC free article] [PubMed] [Google Scholar]

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