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Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse

ABSTRACT: Relapse of AML occurs in up to 50% of patients after allogeneic hematopoietic stem cell transplant (HCT) and heralds an extremely poor prognosis. Cytokine induced memory-like (CIML) human NK cells have enhanced ability to recognize and kill leukemia targets. We initiated a phase I trial of CIML NK cells to treat patients with relapsed myeloid malignancies after haplo-HCT (NCT04024761). Transcriptional profiling analysis by scRNAseq were used to characterize the immunophenotypes of infused NK cells post cell adoptive transfer and as well as their interactions with tumor cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198141 | GEO | 2022/03/11

REPOSITORIES: GEO

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Peri-transplant Glucocorticoids Redistribute Donor T-cells to the Bone Marrow and Prevent Relapse after haploidentical SCT

Project description:Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency.

2021-10-31 | GSE184963 | GEO

Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse

Project description:Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse

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Itacitinib for Prevention of Graft-Versus-Host Disease and Cytokine Release Syndrome with T-cell Replete Peripheral Blood Haploidentical Transplantation

Project description:Haploidentical hematopoietic cell transplantation (haplo-HCT) is an increasingly used treatment for hematologic malignancies. Although post-transplant cyclophosphamide (PtCy) has improved graft vs. host disease (GvHD) prophylaxis in haplo-HCT, patients continue to experience life-threatening complications. IFN-γ and IL-6 are central in the pathophysiology of GvHD and cytokine release syndrome (CRS), and both cytokines signal through Janus kinase (JAK)-1. We tested the effect of adding the JAK-1 selective inhibitor, itacitinib, to PtCy-haplo-HCT to mitigate these complications and improve overall survival. This open-label, single-arm study evaluated the safety and efficacy of itacitinib combined with standard GvHD prophylaxis after haplo-HCT. A total of 42 patients were treated with itacitinib 200 mg daily from day -3 through +100 or +180, followed by a taper. Itacitinib resulted in low CRS grades, all patients had grade 0 (22%) or grade 1 (78%) CRS and there were no cases of grade 2-5 CRS. There were no cases of primary graft failure. No patients developed grade 3-4 aGvHD through day +180. The cumulative incidence of grade 2 aGvHD at day +100 was 21.9%. The 1-year cumulative incidence of moderate or severe chronic GvHD was 5%. The cumulative incidence of relapse at 2 years was 14%. Overall survival (OS) at 1 year was 80%. The cumulative incidence of nonrelapse mortality at day 180 was 8%. Itacitinib, when added to standard GvHD prophylaxis, was well tolerated and resulted in low rates of CRS, acute and chronic GvHD, NRM and encouraging rates of GvHD-free relapse-free survival (GRFS) and OS after haplo-HCT.

2024-11-15 | GSE282021 | GEO

Decrease post-transplant relapse using donor-derived expanded NK-cells.

Project description:In this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 105-1 × 108 cells/kg/dose) were administered on days -2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 ( https://clinicaltrials.gov/ct2/show/NCT01904136 ).

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Murine Allogeneic CAR-T Cells Integrated Before or Early After Posttransplant Cyclophosphamide Exert Anti-Tumor Effects

Project description:The direct integration of chimeric-antigen-receptor (CAR) T cell with allogeneic hematopoietic cell transplantation (allo-HCT) carries the risk of graft-versus-host disease (GVHD) induction by allogeneic CAR-T cells. Based on our past experiments, it has been shown that post-transplantation cyclophosphamide (PTCy) prevents GVHD induction by other cell infusions after T-cell-replete MHC-haploidentical murine allo-HCT models. In this study, we investigated whether CAR-T cells, given in a similar manner in the same MHC-haploidentical murine allo-HCT model, could safely exert anti-tumor effects. We showed that anti-CD19 CAR-T cells administered early after (day +5 of transplant) or prior to (day 0 of transplant) PTCy for allo-HCT cleared leukemia without toxicity or GVHD exacerbation. Using next generation single-cell RNA sequencing approaches, we demonstrated that in comparison to CAR-T cells infused early after PTCy (day +5), CAR-T cells infused prior to PTCy (day 0) exhibited transcriptional changes consistent with increased CD4+ T-cell activation and CD8+ T-cell cytotoxicity.

2022-10-09 | GSE214788 | GEO

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

Project description:BackgroundResponses 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.MethodsWe 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.ResultsIn 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.ConclusionGiven 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 RegistrationClinicalTrials.gov NCT04024761.FundingDunkin' Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.

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Long-Term Persistence of Donor Alveolar Macrophages in Human Lung Transplant Recipients That Influences Donor-Specific Immune Responses.

Project description:Steady-state alveolar macrophages (AMs) are long-lived lung-resident macrophages with sentinel function. Evidence suggests that AM precursors originate during embryogenesis and populate lungs without replenishment by circulating leukocytes. However, their presence and persistence are unclear following human lung transplantation (LTx). Our goal was to examine donor AM longevity and evaluate whether AMs of recipient origin seed the transplanted lungs. Origin of AMs was accessed using donor-recipient HLA mismatches. We demonstrate that 94-100% of AMs present in bronchoalveolar lavage (BAL) were donor derived and, importantly, AMs of recipient origin were not detected. Further, analysis of BAL cells up to 3.5 years post-LTx revealed that the majority of AMs (>87%) was donor derived. Elicitation of de novo donor-specific antibody (DSA) is a major post-LTx complication and a risk factor for development of chronic rejection. The donor AMs responded to anti-HLA framework antibody (Ab) with secretion of inflammatory cytokines. Further, in an experimental murine model, we demonstrate that adoptive transfer of allogeneic AMs stimulated humoral and cellular immune responses to alloantigen and lung-associated self-antigens and led to bronchiolar obstruction. Therefore, donor-derived AMs play an essential role in the DSA-induced inflammatory cascade leading to obliterative airway disease of the transplanted lungs.

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Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

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DNA Methylation Dynamics in Blood after Hematopoietic Cell Transplant

Project description:Classically, epigenetic deregulation is considered a common hallmark of cancer. Nevertheless, recent publications have demonstrated its association with a large array of human diseases such as autoimmune disorders and environmental factors such as diet. Despite the increasing relevance of DNA methylation for the study of critical biological processes and for the development of novel biomarkers, DNA methylation analysis applied to the study of hematopoietic cell transplantation (HCT) has not yet been explored. Here, we analyzed global DNA methylation in blood samples by using a pyrosequencing based methylation assay of repetitive DNA elements (LINE1 and NBL2) in a cohort of 47 patients with allogenic HCT up to 12 months post-HCT. We observed that the recipients stably maintained the donor’s global methylation levels after transplant. Nonetheless, NBL2 methylation is affected by physiopathological events such as development of mixed chimerism. Microarray-based DNA methylation analysis of promoters revealed that methylation in more than 200 genes is altered 1 month post-HCT when compared with non-pathological methylation levels in the donor’s blood. Interestingly, this number dramatically decreased by 6 months post-HCT. Finally, based in the microarray data, we analyzed by pyrosequencing DNA methylation in IFN-γ, FASL, and IL-10 and found a statistically significant association between methylation in these immune genes and the severity of the acute graft-versus-host disease. In conclusion, our results provide strong evidence that DNA methylation changes in blood are linked to underlying physiological events and demonstrate that DNA methylation analysis is a viable strategy for the study of hematopoietic cell transplantation and for development of biomarkers.

2013-02-27 | GSE36832 | GEO

Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [17941R-18740R]

Project description:Lymphocyte subsets (CD8, CD4 Tconv, NK cells) were sorted from patients' peripheral blood obtained on day 28 after haploidentical-donor allogeneic bone marrow transplantation followed by posttransplant cyclophosphamide (PTCy), tacrolimus, and MMF as GVHD prophylaxis (NCT00796562). Cohort of patients developed GVHD, or remained GVHD-free. Cohort of patients developed disease relapse, or remained relapse-free. RNA-sequencing was performed to analyze the transcriptional landscape of alloresponse in post-PTCy breakthrough GVHD and relapse.

2021-09-28 | GSE182612 | GEO

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