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NK Cells and ??T Cells for Relapse Protection After Allogeneic Hematopoietic Cell Transplantation (HCT).

ABSTRACT: Purpose of review:The outcome of allogeneic stem cell transplantation (allo-HCT) is still compromised by relapse and complications. NK cells and ??T cells, effectors which both function through MHC-unrestricted mechanisms, can target transformed and infected cells without inducing Graft-versus-Host Disease (GVHD). Allo-HCT platforms based on CD34+ selection or ??-TCR depletion result in low grades of GVHD, early immune reconstitution (IR) of NK and ??T cells and minimal usage of GVHD prophylaxis. In this review we will discuss strategies to retain and expand the quantity, diversity and functionality of these reconstituting innate cell types. Recent findings:Bisphosphonates, IL-15 cytokine administration, specific antibodies, checkpoint inhibitors and (CMV based) vaccination are currently being evaluated to enhance IR. All these approaches have shown to potentially enhance both NK and ??T cell immuno-repertoires. Summary:Rapidly accumulating data linking innate biology to proposed clinical immune interventions, will give unique opportunities to unravel shared pathways which determine the Graft-versus-Tumor effects of NK and ??T cells.

SUBMITTER: de Witte MA

PROVIDER: S-EPMC5791765 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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NK Cells and γδT Cells for Relapse Protection After Allogeneic Hematopoietic Cell Transplantation (HCT).

de Witte Moniek A MA Kuball Jürgen J Miller Jeffrey S JS

Current stem cell reports 20171016 4

<h4>Purpose of review</h4>The outcome of allogeneic stem cell transplantation (allo-HCT) is still compromised by relapse and complications. NK cells and γδT cells, effectors which both function through MHC-unrestricted mechanisms, can target transformed and infected cells without inducing Graft-versus-Host Disease (GVHD). Allo-HCT platforms based on CD34+ selection or αβ-TCR depletion result in low grades of GVHD, early immune reconstitution (IR) of NK and γδT cells and minimal usage of GVHD pro ...[more]

PMID: 29399441

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Project description:A failed graft-versus-tumor (GVT) effect is a common mechanism of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Although targeting the PD-1/PD-L1 axis may restore GVT effects, PD-1 blockade exacerbates graft-versus-host disease (GVHD) in murine models, and severe GVHD can occur in patients treated with anti-PD-1 therapy after alloHCT. Therefore, we developed a prospective study to assess the safety and efficacy of pembrolizumab in patients relapsing after alloHCT. Eligible patients received pembrolizumab (200 mg every 3 weeks) for up to 2 years. Twelve patients were enrolled (8 patients with acute myeloid leukemia, 1 patient with myelodysplastic syndrome, 1 patient with classical Hodgkin lymphoma, and 2 patients with diffuse large B-cell lymphoma [DLBCL]). All participants received reduced-intensity preparative regimens with in vivo T-cell depletion. The median time from alloHCT to enrollment was 587 days (range, 101-4211). Three participants (25%) experienced grade 3 to 4 immune-related adverse events (irAE) (pneumonitis, 2 patients; hyperthyroidism, 1 patient), all occurring after 1 to 2 cycles, and resolving after pembrolizumab discontinuation and corticosteroid treatment. irAEs of any grade occurred in 5 patients (42%). No treatment-emergent GVHD was observed. Overall and complete response (CR) rates were 22% (2/9). Both patients achieving CRs had PD-L1 gene-amplified lymphomas and diffuse PD-L1 expression on pretreatment biopsies. An acquired EZH2 mutation was identified at relapse in a patient with DLBCL who achieved an initial CR to pembrolizumab, which was associated with downregulated HLA expression on malignant B cells, implicating EZH2 mutations as a potential immune escape mechanism after PD-1-blockade therapy. In conclusion, after alloHCT, treatment with pembrolizumab is feasible and associated with objective responses in relapsed lymphoid malignancies but can induce severe irAEs, requiring vigilant monitoring. This trial was registered at www.clinicaltrials.gov as #NCT02981914.

Dataset Information

NK Cells and ??T Cells for Relapse Protection After Allogeneic Hematopoietic Cell Transplantation (HCT).

Publications

NK Cells and γδT Cells for Relapse Protection After Allogeneic Hematopoietic Cell Transplantation (HCT).

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