Early and Sustained Expansion of Adaptive Natural Killer Cells Following Haploidentical Transplantation and CTLA4Ig-Primed Donor Lymphocyte Infusions Dissociate Graft-versus-Leukemia and Graft-versus-Host Effects

Jaiswal, Sarita Rani; Chakraborty, Sushmita; Lakhchaura, Rohit; Shashi, Pooja; Mehta, Anupama; Soni, Mayank; Chakrabarti, Suparno

doi:10.1016/j.jtct.2020.10.005

Cited by 15 publications

(20 citation statements)

References 32 publications

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“…NKG2C+ NK cells were detectable past 3 months and effectively killed HLA-E expressing tumor targets despite their poor response to IL-12/IL-18 and low production of interferon-γ (IFN-γ). Clinical studies showed that therapy with adaptive NKG2C+ NK cells was associated with lower DP after transplant in a study of adult patients with advanced acute leukemia [ 51 , 52 ]. However, the clinical benefit of NKG2C+ NK cells in leukemia has been disputed by other groups [ 53 ] and no studies to date have targeted this receptor in pediatric solid tumors indicating the need for further investigation.…”

Section: Nk Cell Activating and Inhibitory Receptorsmentioning

confidence: 99%

Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

Quamine

Olsen

Cho

et al. 2021

Cancers

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Treatment of metastatic pediatric solid tumors remain a significant challenge, particularly in relapsed and refractory settings. Standard treatment has included surgical resection, radiation, chemotherapy, and, in the case of neuroblastoma, immunotherapy. Despite such intensive therapy, cancer recurrence is common, and most tumors become refractory to prior therapy, leaving patients with few conventional treatment options. Natural killer (NK) cells are non-major histocompatibility complex (MHC)-restricted lymphocytes that boast several complex killing mechanisms but at an added advantage of not causing graft-versus-host disease, making use of allogeneic NK cells a potential therapeutic option. On top of their killing capacity, NK cells also produce several cytokines and growth factors that act as key regulators of the adaptive immune system, positioning themselves as ideal effector cells for stimulating heavily pretreated immune systems. Despite this promise, clinical efficacy of adoptive NK cell therapy to date has been inconsistent, prompting a detailed understanding of the biological pathways within NK cells that can be leveraged to develop “next generation” NK cell therapies. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors.

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Section: Nk Cell Activating and Inhibitory Receptorsmentioning

confidence: 99%

Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

Quamine

Olsen

Cho

et al. 2021

Cancers

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“…In this context, it is worth noting that inversion of NKG2C and NKG2A expressions following EBV reactivations, in the context of allogeneic HCT, strongly predisposed to chronic graft-versushost disease (23). The same was demonstrated in the context of acute GVHD as well (7,24). In contrast to conventional NK cells, which are suppressed by regulatory T cells (Tregs), ANK cells are inherently resistant to Treg-mediated suppression and vice-versa (25).…”

Section: Discussionmentioning

confidence: 91%

“…At the early stages of COVID-19 pandemic, our group had hypothesised that ANK cells might have a significant impact on the severity and outcome of infection with SARS-CoV-2 (5). This was based on our observations of strong correlation between an anti-leukemia as well as an antiviral effect of ANK cells derived from CMV-seropositive donors (6)(7)(8). Subsequently, a few studies have studied the NK cell profile in COVID-19 patients during the acute phase (9).…”

Section: Introductionmentioning

confidence: 99%

Impact Of Adaptive Natural Killer Cells, KLRC2 Genotype and Cytomegalovirus Reactivation On Late Mortality In Patients With Severe Covid-19 Lung Disease

Jaiswal

Arunachalam²,

Bhardwaj

et al. 2021

Preprint

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Objective: COVID-19 infection results in severe lung disease in a small but significant number of infected patients. The etiopathogenesis in a subset of such patients, who continue to have progressive pulmonary disease following virus clearance remains unexplored. Methods: We investigated the role of NKG2C+/NKG2A- adaptive natural killer (ANK) cells, KLRC2 genotype and cytomegalovirus reactivation in 22 such patients. Results: The median duration of virus positivity was 23 days and the median duration of hospitalisation was 48 days. The overall survival at 60 days in this group was 50%. Older age and comorbidities impacted survival negatively. CMV viremia was documented in 11 patients, with a survival of 25% vs 80% in those without viremia with viral load correlating with mortality. ANK cells were markedly depressed in all patients at day 15. However, persistently low ANK cells at 30 days along with an inversely high NKG2C-/NKG2A+ inhibitory NK cells significantly correlated with high CMV viremia as well as mortality, irrespective of KLRC2 genotype. Day 30 ANK cells were significantly lower in KLRC2 deletion group. IFN-gamma and Perforin release were severely compromised in all patients at day +15, with significant improvement in the survivors at day +30, but not in those with adverse outcome. Conclusion: Patients with severe lung disease even after negative SARS-CoV-2 status, with persistently reduced and functionally compromised ANK cells, are more likely to have CMV reactivation and an adverse outcome, independent of KLRC2 genotype.

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“…In summary, the successful application of new strategies following allografting (15,137,142,144), such as rhG-CSF combined with minimal-dose Dec, Aza plus VEN (NCT04809181), and targeted agent maintenance, could help AML patients avoid hematological relapse as much as possible, thus decreasing the CIR and improving the survival rate (Figure 2B).…”

Section: Could We Incorporate Other Approaches For Aml Relapse Treatment and Prevention After Haplo-sct?mentioning

confidence: 99%

Haploidentical Stem Cell Transplantation for Acute Myeloid Leukemia: Current Therapies, Challenges and Future Prospective

Chang

Zhao

2021

Front. Oncol.

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Haploidentical stem cell transplantation (haplo-SCT), an alternative donor source, offers a curative therapy for patients with acute myeloid leukemia (AML) who are transplant candidates. Advances in transplantation techniques, such as donor selection, conditioning regimen modification, and graft-versus-host disease prophylaxis, have successfully improved the outcomes of AML patients receiving haplo-SCT and extended the haploidentical transplant indictions for AML. Presently, treating de novo AML, secondary AML, therapy-related AML and refractory and relapsed AML with haplo-SCT can achieve comparable outcomes to those of human leukocyte antigen (HLA)-matched sibling donor transplantation (MSDT), unrelated donor transplantation or umbilical cord blood transplantation. For some subgroups of AML subjects, such as patients with positive pretransplantation minimal/measurable residual disease, recent studies suggest that haplo-SCT might be superior to MSDT in decreasing relapse and improving survival. Unfortunately, for patients with AML after haplo-SCT, relapse and infections remain the causes of death that restrict further improvement in clinical outcomes. In this review, we discuss the recent advances and challenges in haplo-SCT for AML treatment, mainly focusing on unmanipulated haplo-SCT protocols. We provide an outlook on future prospects and suggest that relapse prophylaxis, intervention, and treatment, as well as infection prevention and therapy, are areas of active research in AML patients who receive haploidentical allografts.

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Early and Sustained Expansion of Adaptive Natural Killer Cells Following Haploidentical Transplantation and CTLA4Ig-Primed Donor Lymphocyte Infusions Dissociate Graft-versus-Leukemia and Graft-versus-Host Effects

Cited by 15 publications

References 32 publications

Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

Impact Of Adaptive Natural Killer Cells, KLRC2 Genotype and Cytomegalovirus Reactivation On Late Mortality In Patients With Severe Covid-19 Lung Disease

Haploidentical Stem Cell Transplantation for Acute Myeloid Leukemia: Current Therapies, Challenges and Future Prospective

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