With the increasing utility of hematopoietic stem cell transplantation (SCT) as a treatment for cancer and noncancerous disorders, more challenges and complications associated with SCT have emerged. ...Renal injury immediately after transplant is common and well understood, but long-term renal injury is becoming more evident. Chronic graft-versus-host disease (GVHD) is a known long-term complication of SCT, and membranous nephropathy (MN) is emerging as the most common cause of SCT-associated glomerular pathology. In this case report, we present a patient who developed features of anti-PLA2R antibody-negative MN following autologous SCT. The renal injury responded well to steroids and further response to rituximab therapy was noted, suggesting antibody-mediated autoimmune glomerular disease. We also present a review of the literature on autologous GVHD and the role of T and B cells in induction of autoimmunity by SCT.
At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)–related portal hypertension after allogeneic ...hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient HVPG >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension. From our institutional database, we identified 40 patients who developed IRA after allo-HSCT between 2004 and 2018. The patients' median age at the time of allo-HSCT was 54 years (range, 21-73 years). The median time to development of IRA after allo-HSCT was 80 days (range, 16-576 days). The median number of paracentesis was 3 (range, 1-11), and 15 (38%) patients had an intraperitoneal catheter placed for continued drainage of the rapidly accumulating ascites. Portal pressures were measured in 19 patients; 6 (15%) had moderate portal hypertension (HVPG 6-9 mm Hg), and 13 (33%) had severe portal hypertension (HVPG ≥ 10 mm Hg). Liver biopsy was performed in 24 patients. None of the patients met the criteria for classical VOD/SOS (clinical/histological) or cirrhosis (histological). The cumulative incidence of nonrelapse mortality was 63%, and the median survival duration after the development of the IRA was 7 months (range, 0.8-125.6 months). IRA is a poorly understood and often fatal complication of allo-HSCT.
•IRA is an unrecognized fatal complication of allo-HSCT not reported before.•Incidence of IRA is 1% and IRA is fatal in 63% of cases.
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Immune suppression after oncologic surgery is a common phenomenon. Several studies have demonstrated that it is associated with poor survival owing to cancer progression. Immunotherapy, especially NK ...cell transfer therapy, is an attractive alternative because current methodologies to isolate, generate, and expand NK cells have shown good safety profiles in current active investigations. We believe that the use of NK cell transfer therapy in the context of postoperative minimal residual disease deserves significant investigation.
•In acute myeloid leukemia patients undergoing allogeneic transplant, minimal residual disease–based risk stratification identifies patients at a high risk of relapse.•Minimal residual disease–based ...risk stratification should be used for individualized management approach for post-transplant management of relapse.
We studied if the inclusion of early post–stem cell transplantation (SCT) minimal residual disease (MRD) assessments improved prognostication in patients with acute myeloid leukemia (AML). Two hundred sixty-nine AML patients in morphological complete remission (CR) who underwent a first SCT were included if they had evaluable pre-SCT MRD assessment by multiparametric flow cytometry. Post-SCT MRD assessments were performed at days +30, +100, and +180. The primary outcome was 1-year relapse incidence (RI). Of 269 patients in CR, 83 (30.8%) had detectable MRD pre-SCT. Post-SCT, during routine disease assessment time points, 9 of 241 evaluable patients (3.7%) at day +30, 6 of 191 evaluable patients (3.1%) at day +100, and 4 of 133 evaluable patients (3%) at day +180 were MRD positive while in CR. MRD positivity at day +30 predicted the highest risk of relapse at 1 year (group 1, 1-year RI 78%). Among MRD-negative patients at day +30, either adverse risk category by European Leukemia Net (ELN) or intermediate risk who were aged ≥60 years and/or pre-SCT MRD-positive represented the intermediate-risk group (group 2, 1-year RI 29%). The remaining patients represented the low-risk group (group 3, 1-year RI 5%). For patients in CR beyond day +30 post-SCT, detectable MRD at any time point predicted impending relapse within 2 months. Early post-SCT MRD assessment—combined with pre-SCT MRD assessment, ELN risk category, and age—improves risk stratification for relapse in AML patients post-transplant. Studies aimed at preventing impending relapse in this high-risk population are urgently needed.
Cytomegalovirus (CMV) reactivation is one of the most common infectious complications after allogeneic hematopoietic cell transplant (HCT) and may result in significant morbidity and mortality. ...Primary prophylaxis with letermovir demonstrated a reduction in clinically significant CMV infections (CS-CMVi) in clinical trials of CMV-seropositive HCT recipients. This study aims at exploring the effect of primary letermovir prophylaxis in this population on the incidence and outcomes of refractory or resistant CMV infections.
This is a single-center, retrospective cohort study of 537 consecutive CMV-seropositive allogeneic HCT recipients cared for between March 2016 and October 2018. Baseline demographics, HCT characteristics, CMV infections, treatment, and mortality data were collected from the electronic medical record. CMV outcomes were defined according to the recently standardized definitions for clinical trials. Characteristics and outcomes were assessed according to receipt of primary letermovir prophylaxis.
Of 537 patients identified, 123 received letermovir for primary prophylaxis during the first 100 days after HCT; 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with reductions in CS-CMVi (hazard ratio HR 0.26; 95% confidence interval CI, 0.16-0.41), CMV end-organ disease (HR 0.23; 95% CI, 0.10-0.52), refractory or resistant CMV infection (HR 0.15; 95% CI, 0.04-0.52), and nonrelapse mortality at week 48 (HR 0.55; 95% CI, 0.32-0.93). There was neither resistant CMV nor CMV-related mortality in the primary letermovir prophylaxis group.
Primary letermovir prophylaxis effectively prevents refractory or resistant CMV infections and decreases nonrelapse mortality at week 48, as well as CS-CMVi and CMV disease after allogeneic HCT.
A sequentially adaptive Bayesian design is presented for a clinical trial of cord blood-derived natural killer cells to treat severe haematologic malignancies. Given six prognostic subgroups defined ...by disease type and severity, the goal is to optimize cell dose in each subgroup. The trial has five co-primary outcomes: the times to severe toxicity, cytokine release syndrome, disease progression or response and death. The design assumes a multivariate Weibull regression model, with marginals depending on dose, subgroup and patient frailties that induce association between the event times. Utilities of all possible combinations of the non-fatal outcomes over the first 100 days following cell infusion are elicited, with posterior mean utility used as a criterion to optimize the dose. For each subgroup, the design stops accrual to doses having an unacceptably high death rate and at the end of the trial selects the optimal safe dose. A simulation study is presented to validate the design's safety, ability to identify optimal doses and robustness, and to compare it with a simplified design that ignores patient heterogeneity.
Summary
Multiple myeloma (MM) is a disease with known immune dysregulation. Natural killer (NK) cells have shown preclinical activity in MM. We conducted a first‐in‐human study of umbilical cord ...blood‐derived (CB) NK cells for MM patients undergoing high dose chemotherapy and autologous haematopoietic stem cell transplantation (auto‐HCT). Patients received lenalidomide (10 mg) on days −8 to −2, melphalan 200 mg/m2 on day −7, CB‐NK cells on day −5 and auto‐HCT on day 0. Twelve patients were enrolled, three on each of four CB‐NK cell dose levels: 5 × 106, 1 × 107, 5 × 107 and 1 × 108 CB‐NK cells/kg. Ten patients had either high‐risk chromosomal changes or a history of relapsed/progressed disease. There were no infusional toxicities and no graft‐versus‐host disease. One patient failed to engraft due to poor autologous graft quality and was rescued with a back‐up autologous graft. Overall, 10 patients achieved at least a very good partial response as their best response, including eight with near complete response or better. With a median follow‐up of 21 months, four patients have progressed or relapsed, two of whom have died. CB‐NK cells were detected in vivo in six patients, with an activated phenotype (NKG2D+/NKp30+). These data warrant further development of this novel cellular therapy.
T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically ...modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR.
T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19).
SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients.
CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.
Autologous, NCT00968760; allogeneic, NCT01497184; long-term follow-up, NCT01492036.
National Cancer Institute, private foundations, and institutional funds. Please see Acknowledgments for details.
A Bayesian feature allocation model (FAM) is presented for identifying cell subpopulations based on multiple samples of cell surface or intracellular marker expression level data obtained by ...cytometry by time of flight (CyTOF). Cell subpopulations are characterized by differences in marker expression patterns, and cells are clustered into subpopulations based on their observed expression levels. A model-based method is used to construct cell clusters within each sample by modeling subpopulations as latent features, using a finite Indian buffet process. Non-ignorable missing data due to technical artifacts in mass cytometry instruments are accounted for by defining a static missingship mechanism. In contrast with conventional cell clustering methods, which cluster observed marker expression levels separately for each sample, the FAM-based method can be applied simultaneously to multiple samples, and also identify important cell subpopulations likely to be otherwise missed. The proposed FAM-based method is applied to jointly analyse three CyTOF datasets to study natural killer (NK) cells. Because the subpopulations identified by the FAM may define novel NK cell subsets, this statistical analysis may provide useful information about the biology of NK cells and their potential role in cancer immunotherapy which may lead, in turn, to development of improved NK cell therapies.
Abstract
Background:
Cure rates for osteosarcoma (OS) have not improved in >30 years and no new effectivetherapies have been identified for metastatic disease. Natural killer (NK) cells have become ...an attractive tool for cancer immunotherapy. Efficay is improved by direct tumor targeting introducing a specific chimeric antigen receptor (CAR). Emerging knowledge suggests CD70 to be a viable candidate as expression is higher in lung metastases and it has been correlated with tumor escape from immune surveillance.
Objective:
To assess whether using CD70 CAR-NK cells we can enhance trafficking, homing and proliferation of NK cells and therefore therapeutic efficacy against OS.
Methods:
We analyzed the cBioportal database to verify CD70 expression in OS. Surface expression of CD70 on human OS cell lines and normal osteoblasts was determined by flow cytometry. CD70 CAR constructs were sequenced, verified and transduced into NK cells. CD70 CAR NK and control NK cells cytolytic activity against OS cells was evaluated by IncuCyte. In vitrocytokine release was measured upon CD70 CAR NK/NK cells exposure to OS cells (IsoPlexis).
Results:
Database analysis confirmed OS CD70 gene amplification. Flow cytometry showed variable expression of CD70 on OS cells and no expression on human osteoblasts. There was an increase in CD70 CAR NK percent lysis against OS cells at the highest effector:target ratios compared to control NK cells. We found a predominant release in the chemoattractive/stimulatory cytokines upon OS cells exposure to CD70 CAR NK cells.
Conclusion:
CD70 has immunotherapy potential against OS. CD70 CAR NK cells have increased cytolytic activity against OS cells in vitro. Cytolytic activity may be influenced by the release of specific cytokines.
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