RESUMO
Innate immune responses that allow hosts to survive infection depend on the action of multiple conserved signaling pathways. Pathogens and parasites in turn have evolved virulence factors to target these immune signaling pathways in an attempt to overcome host immunity. Consequently, the interactions between host immune molecules and pathogen virulence factors play an important role in determining the outcome of an infection. The immune responses of Drosophila melanogaster provide a valuable model to understand immune signaling and host-pathogen interactions. Flies are commonly infected by parasitoid wasps and mount a coordinated cellular immune response following infection. This response is characterized by the production of specialized blood cells called lamellocytes that form a tight capsule around wasp eggs in the host hemocoel. The conserved JAK-STAT signaling pathway has been implicated in lamellocyte proliferation and is required for successful encapsulation of wasp eggs. Here we show that activity of Stat92E, the D. melanogaster STAT ortholog, is induced in immune tissues following parasitoid infection. Virulent wasp species are able to suppress Stat92E activity during infection, suggesting they target JAK-STAT pathway activation as a virulence strategy. Furthermore, two wasp species (Leptopilina guineaensis and Ganaspis xanthopoda) suppress phenotypes associated with a gain-of-function mutation in hopscotch, the D. melanogaster JAK ortholog, indicating that they inhibit the activity of the core signaling components of the JAK-STAT pathway. Our data suggest that parasitoid wasp virulence factors block JAK-STAT signaling to overcome fly immune defenses.
Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Interações Hospedeiro-Parasita , Janus Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Vespas , Animais , Drosophila melanogaster/parasitologia , Fatores de Transcrição STAT/metabolismo , Janus Quinases/metabolismo , Virulência , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Imunidade InataRESUMO
ABSTRACT: Human herpesvirus 6B (HHV-6B) reactivation and disease are increasingly reported after chimeric antigen receptor (CAR) T-cell therapy (CARTx). HHV-6 reactivation in the CAR T-cell product was recently reported, raising questions about product and patient management. Because of overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide 2 lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks after infusion, HHV-6B reactivation occurred in 8 of 89 participants; 3 had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval [CI], 2.2-12.5). HHV-6B detection was low level (median peak, 435 copies per mL; interquartile range, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in the blood and/or cerebrospinal fluid (CSF) within 12 weeks after infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing, with detection in 1. Among 34 patients with CSF HHV-6 testing, 1 patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.
Assuntos
Herpesvirus Humano 6 , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Infecções por Roseolovirus , Ativação Viral , Humanos , Herpesvirus Humano 6/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Infecções por Roseolovirus/imunologia , Infecções por Roseolovirus/virologia , Infecções por Roseolovirus/terapia , Infecções por Roseolovirus/diagnóstico , Receptores de Antígenos Quiméricos/imunologia , Ativação Viral/imunologia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Idoso , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem , IncidênciaRESUMO
BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).
Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina/efeitos adversos , Alanina/uso terapêutico , Antivirais/efeitos adversos , COVID-19/complicações , COVID-19/mortalidade , Comorbidade , Progressão da Doença , Método Duplo-Cego , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , SARS-CoV-2/efeitos dos fármacos , Tempo para o Tratamento , Carga ViralRESUMO
BACKGROUND: Plasma microbial cell-free DNA sequencing (mcfDNA-Seq) is a noninvasive test for microbial diagnosis of invasive mold infection (IMI). The utility of mcfDNA-Seq for predicting IMI onset and the clinical implications of mcfDNA concentrations are unknown. METHODS: We retrospectively tested plasma from hematopoietic cell transplant (HCT) recipients with pulmonary IMI and ≥1 mold identified by mcfDNA-Seq in plasma collected within 14 days of clinical diagnosis. Samples collected from up to 4 weeks before and 4 weeks after IMI diagnosis were evaluated using mcfDNA-Seq. RESULTS: Thirty-five HCT recipients with 39 IMIs (16 Aspergillus and 23 non-Aspergillus infections) were included. Pathogenic molds were detected in 38%, 26%, 11%, and 0% of samples collected during the first, second, third, and fourth week before clinical diagnosis, respectively. In non-Aspergillus infections, median mcfDNA concentrations in samples collected within 3 days of clinical diagnosis were higher in infections with versus without extrapulmonary spread (4.3 vs 3.3 log10 molecules per microliter [mpm], P = .02), and all patients (8/8) with mcfDNA concentrations >4.0 log10 mpm died within 42 days after clinical diagnosis. CONCLUSIONS: Plasma mcfDNA-Seq can identify pathogenic molds up to 3 weeks before clinical diagnosis of pulmonary IMI. Plasma mcfDNA concentrations may correlate with extrapulmonary spread and mortality in non-Aspergillus IMI.
Assuntos
Ácidos Nucleicos Livres , Transplante de Células-Tronco Hematopoéticas , Humanos , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fungos , Pulmão , Aspergillus/genéticaRESUMO
The immunocompromised population was disproportionately affected by the SARS-CoV-2 pandemic. However, these individuals were largely excluded from clinical trials of vaccines, monoclonal antibodies, and small molecule antivirals. While the community of scientists, clinical researchers, and funding agencies have proven that these therapeutics can be made and tested in record time, extending this progress to vulnerable and medically complex individuals from the start has been a missed opportunity. Here we advocate that it is paramount to plan for future pandemics by investing in specific clinical trial infrastructure for the immunocompromised population to be prepared when the need arises.
RESUMO
BACKGROUND: Hematopoietic cell transplant (HCT) or chimeric antigen receptor (CAR) T-cell therapy recipients have high morbidity from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are limited data on outcomes from SARS-CoV-2 infection shortly before cellular therapy and uncertainty whether to delay therapy. METHODS: We conducted a retrospective cohort study of patients with SARS-CoV-2 infection within 90 days before HCT or CAR-T-cell therapy between January 2020 and November 2022. We characterized the kinetics of SARS-CoV-2 detection, clinical outcomes following cellular therapy, and impact on delays in cellular therapy. RESULTS: We identified 37 patients (n = 15 allogeneic HCT, n = 11 autologous HCT, n = 11 CAR-T-cell therapy) with SARS-CoV-2 infections within 90 days of cellular therapy. Most infections (73%) occurred between March and November 2022, when Omicron strains were prevalent. Most patients had asymptomatic (27%) or mild (68%) coronavirus disease 2019 (COVID-19). SARS-CoV-2 positivity lasted a median of 20.0 days (interquartile range, 12.5-26.25 days). The median time from first positive SARS-CoV-2 test to cellular therapy was 45 days (interquartile range, 37.75-70 days); 1 patient tested positive on the day of infusion. After cellular therapy, no patients had recrudescent SARS-CoV-2 infection or COVID-19-related complications. Cellular therapy delays related to SARS-CoV-2 infection occurred in 70% of patients for a median of 37 days. Delays were more common after allogeneic (73%) and autologous (91%) HCT compared to CAR-T-cell therapy (45%). CONCLUSIONS: Patients with asymptomatic or mild COVID-19 may not require prolonged delays in cellular therapy in the context of contemporary circulating variants and availability of antiviral therapies.
Assuntos
COVID-19 , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , SARS-CoV-2 , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , COVID-19/terapia , COVID-19/imunologia , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2/imunologia , Adulto , Imunoterapia Adotiva/métodos , Idoso , Receptores de Antígenos Quiméricos/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor-modified T-cell immunotherapy (CARTx) is poorly understood owing to a lack of routine surveillance. METHODS: We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx recipients and tested plasma samples for CMV before and weekly up to 12 weeks after CARTx. We assessed CMV-specific cell-mediated immunity (CMV-CMI) before and 2 and 4 weeks after CARTx, using an interferon γ release assay to quantify T-cell responses to IE-1 and pp65. We tested pre-CARTx samples to calculate a risk score for cytopenias and infection (CAR-HEMATOTOX). We used Cox regression to evaluate CMV risk factors and evaluated the predictive performance of CMV-CMI for CMV reactivation in receiver operator characteristic curves. RESULTS: CMV was detected in 1 patient (1.4%) before and in 18 (25%) after CARTx, for a cumulative incidence of 27% (95% confidence interval, 16.8-38.2). The median CMV viral load (interquartile range) was 127 (interquartile range, 61-276) IU/mL, with no end-organ disease observed; 5 patients received preemptive therapy based on clinical results. CMV-CMI values reached a nadir 2 weeks after infusion and recovered to baseline levels by week 4. In adjusted models, BCMA-CARTx (vs CD19/CD20) and corticosteroid use for >3 days were significantly associated with CMV reactivation, and possible associations were detected for lower week 2 CMV-CMI and more prior antitumor regimens. The cumulative incidence of CMV reactivation almost doubled when stratified by BCMA-CARTx target and use of corticosteroids for >3 days (46% and 49%, respectively). CONCLUSIONS: CMV testing could be considered between 2 and 6 weeks in high-risk CARTx recipients.
Assuntos
Infecções por Citomegalovirus , Receptores de Antígenos Quiméricos , Adulto , Humanos , Citomegalovirus , Antígeno de Maturação de Linfócitos B , Imunidade Celular , Terapia Baseada em Transplante de Células e TecidosRESUMO
BACKGROUND: The optimal timing of vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines after cellular therapy is incompletely understood. The objectives of this study are to determine whether humoral and cellular responses after SARS-CoV-2 vaccination differ if initiated <4 months versus 4-12 months after cellular therapy. METHODS: We conducted a multicenter, prospective, observational study at 30 cancer centers in the United States. SARS-CoV-2 vaccination was administered as part of routine care. We obtained blood prior to and after vaccinations at up to 5 time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T-cell receptors, in a subgroup. RESULTS: We enrolled 466 allogeneic hematopoietic cell transplantation (HCT) (n = 231), autologous HCT (n = 170), and chimeric antigen receptor T-cell (CAR-T-cell) therapy (n = 65) recipients between April 2021 and June 2022. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months versus 4-12 months after cellular therapy. Anti-S IgG ≥2500â U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T-cell recipients, respectively. SARS-CoV-2-specific T-cell responses were attained in 57%, 83%, and 58%, respectively. Pre-cellular therapy SARS-CoV-2 infection or vaccination and baseline B-cell count were key predictors of post-cellular therapy immunity. CONCLUSIONS: These data support mRNA SARS-CoV-2 vaccination prior to, and reinitiation 3 to 4 months after, cellular therapies with allogeneic HCT, autologous HCT, and CAR-T-cell therapy.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Transplante de Células-Tronco Hematopoéticas , SARS-CoV-2 , Humanos , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Feminino , COVID-19/prevenção & controle , COVID-19/imunologia , SARS-CoV-2/imunologia , Adulto , Anticorpos Antivirais/sangue , Anticorpos Neutralizantes/sangue , Idoso , Vacinação , Imunoterapia Adotiva/métodos , Imunoglobulina G/sangue , Receptores de Antígenos Quiméricos/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Estados UnidosRESUMO
BACKGROUND: Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia. METHODS: In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing. Pneumonia etiology was adjudicated by a blinded independent committee. The primary outcome, additive diagnostic value, was assessed in the Per Protocol population (patients with complete testing results and no major protocol deviations) and defined as the percent of patients with an etiology of pneumonia exclusively identified by plasma microbial cell-free DNA sequencing. Clinical additive diagnostic value was assessed in the Per Protocol subgroup with negative usual care testing. RESULTS: Of 257 patients, 173 met Per Protocol criteria. A pneumonia etiology was identified by usual care in 52/173 (30.1%), plasma microbial cell-free DNA sequencing in 49/173 (28.3%) and the combination of both in 73/173 (42.2%) patients. Plasma microbial cell-free DNA sequencing exclusively identified an etiology of pneumonia in 21/173 patients (additive diagnostic value 12.1%, 95% confidence interval [CI], 7.7% to 18.0%, P < .001). In the Per Protocol subgroup with negative usual care testing, plasma microbial cell-free DNA sequencing identified a pneumonia etiology in 21/121 patients (clinical additive diagnostic value 17.4%, 95% CI, 11.1% to 25.3%). CONCLUSIONS: Non-invasive plasma microbial cell-free DNA sequencing significantly increased diagnostic yield in immunocompromised patients with pneumonia undergoing bronchoscopy and extensive microbiologic and molecular testing. CLINICAL TRIALS REGISTRATION: NCT04047719.
Assuntos
Pneumonia , Adulto , Humanos , Estudos Prospectivos , Pneumonia/etiologia , Análise de Sequência de DNA , Hospedeiro ImunocomprometidoRESUMO
PURPOSE OF REVIEW: Viral infections continue to burden allogeneic hematopoietic cell transplant (HCT) recipients. We review the epidemiology, diagnosis, and management of human herpesvirus (HHV)-6, HHV-8 and parvovirus B19 following HCT. RECENT FINDINGS: Advances in HCT practices significantly improved outcomes but impact viral epidemiology: post-transplant cyclophosphamide for graft-versus-host disease prevention increases HHV-6 reactivation risk while the impact of letermovir for CMV prophylaxis - and resulting decrease in broad-spectrum antivirals - is more complex. Beyond the well established HHV-6 encephalitis, recent evidence implicates HHV-6 in pneumonitis. Novel less toxic therapeutic approaches (brincidofovir, virus-specific T-cells) may enable preventive strategies in the future. HHV-8 is the causal agent of Kaposi's sarcoma, which is only sporadically reported after HCT, but other manifestations are possible and not well elucidated. Parvovirus B19 can cause severe disease post-HCT, frequently manifesting with anemia, but can also be easily overlooked due to lack of routine screening and ambiguity of manifestations. SUMMARY: Studies should establish the contemporary epidemiology of HHV-6, and other more insidious viruses, such as HHV-8 and parvovirus B19 following HCT and should encompass novel cellular therapies. Standardized and readily available diagnostic methods are key to elucidate epidemiology and optimize preventive and therapeutic strategies to mitigate the burden of infection.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 6 , Herpesvirus Humano 8 , Parvovirus B19 Humano , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Parvovirus B19 Humano/isolamento & purificação , Infecções por Parvoviridae/epidemiologia , Infecções por Parvoviridae/diagnóstico , Antivirais/uso terapêutico , Infecções por Roseolovirus/epidemiologia , Infecções por Roseolovirus/virologia , Infecções por Roseolovirus/diagnóstico , Transplante Homólogo/efeitos adversos , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/virologiaRESUMO
CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells are novel therapies showing great promise for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Single-arm studies showed significant variations in outcomes across distinct CD19 CAR T-cell products. To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase 1/2 clinical trial (NCT01865617). After adjustment for age, hematopoietic cell transplantation-specific comorbidity index, lactate dehydrogenase (LDH), largest lesion diameter, and absolute lymphocyte count (ALC), CAR T-cell product type remained associated with outcomes in multivariable models. JCAR014 was independently associated with lower cytokine release syndrome (CRS) severity compared with axicel (adjusted odds ratio [aOR], 0.19; 95% confidence interval [CI]; 0.08-0.46), with a trend toward lower CRS severity with tisacel compared with axicel (aOR, 0.47; 95% CI, 0.21-1.06; P = .07). Tisacel (aOR, 0.17; 95% CI, 0.06-0.48) and JCAR014 (aOR, 0.17; 95% CI, 0.06-0.47) were both associated with lower immune effector cell-associated neurotoxicity syndrome severity compared with axicel. Lower odds of complete response (CR) were predicted with tisacel and JCAR014 compared with axicel. Although sensitivity analyses using either positron emission tomography- or computed tomography-based response criteria also suggested higher efficacy of axicel over JCAR014, the impact of tisacel vs axicel became undetermined. Higher preleukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR. We conclude that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients.
Assuntos
Imunoterapia Adotiva , Linfoma de Células B , Antígenos CD19 , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Síndrome da Liberação de Citocina , Humanos , Linfoma de Células B/terapia , Receptores de Antígenos Quiméricos , Estudos Retrospectivos , Linfócitos TRESUMO
In order to respond to infection, hosts must distinguish pathogens from their own tissues. This allows for the precise targeting of immune responses against pathogens and also ensures self-tolerance, the ability of the host to protect self tissues from immune damage. One way to maintain self-tolerance is to evolve a self signal and suppress any immune response directed at tissues that carry this signal. Here, we characterize the Drosophila tuSz1 mutant strain, which mounts an aberrant immune response against its own fat body. We demonstrate that this autoimmunity is the result of two mutations: 1) a mutation in the GCS1 gene that disrupts N-glycosylation of extracellular matrix proteins covering the fat body, and 2) a mutation in the Drosophila Janus Kinase ortholog that causes precocious activation of hemocytes. Our data indicate that N-glycans attached to extracellular matrix proteins serve as a self signal and that activated hemocytes attack tissues lacking this signal. The simplicity of this invertebrate self-recognition system and the ubiquity of its constituent parts suggests it may have functional homologs across animals.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/imunologia , Proteínas da Matriz Extracelular/metabolismo , Tolerância Imunológica/imunologia , Janus Quinases/metabolismo , Mutação , Tolerância a Antígenos Próprios , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Proteínas da Matriz Extracelular/genética , Glicosilação , Hemócitos , Janus Quinases/genéticaRESUMO
Antibodies against foreign human leukocyte antigen (HLA) molecules are barriers to successful organ transplantation. B cell-depleting treatments are used to reduce anti-HLA antibodies but have limited efficacy. We hypothesized that the primary source for anti-HLA antibodies is long-lived plasma cells, which are ineffectively targeted by B cell depletion. To study this, we screened for anti-HLA antibodies in a prospectively enrolled cohort of 49 patients who received chimeric antigen receptor T-cell therapy (CARTx), targeting naïve and memory B cells (CD19-targeted, n = 21) or plasma cells (BCMA-targeted, n = 28) for hematologic malignancies. Longitudinal samples were collected before and up to 1 year after CARTx. All individuals were in sustained remission. We identified 4 participants with anti-HLA antibodies before CD19-CARTx. Despite B cell depletion, anti-HLA antibodies and calculated panel reactive antibody scores were stable for 1 year after CD19-CARTx. Only 1 BCMA-CARTx recipient had pre-CARTx low-level anti-HLA antibodies, with no follow-up samples available. These data implicate CD19neg long-lived plasma cells as an important source for anti-HLA antibodies, a model supported by infrequent HLA sensitization in BCMA-CARTx subjects receiving previous plasma cell-targeted therapies. Thus, plasma cell-targeted therapies may be more effective against HLA antibodies, thereby enabling improved access to organ transplantation and rejection management.
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Neoplasias Hematológicas , Imunoterapia Adotiva , Humanos , Antígeno de Maturação de Linfócitos B , Antígenos CD19 , Linfócitos BRESUMO
KEY MESSAGE: A novel locus was discovered on chromosome 7 associated with a lesion mimic in maize; this lesion mimic had a quantitative and heritable phenotype and was predicted better via subset genomic markers than whole genome markers across diverse environments. Lesion mimics are a phenotype of leaf micro-spotting in maize (Zea mays L.), which can be early signs of biotic or abiotic stresses. Dissecting its inheritance is helpful to understand how these loci behave across different genetic backgrounds. Here, 538 maize recombinant inbred lines (RILs) segregating for a novel lesion mimic were quantitatively phenotyped in Georgia, Texas, and Wisconsin. These RILs were derived from three bi-parental crosses using a tropical pollinator (Tx773) as the common parent crossed with three inbreds (LH195, LH82, and PB80). While this lesion mimic was heritable across three environments based on phenotypic ([Formula: see text] = 0.68) and genomic ([Formula: see text] = 0.91) data, transgressive segregation was observed. A genome-wide association study identified a single novel locus on chromosome 7 (at 70.6 Mb) also covered by a quantitative trait locus interval (69.3-71.0 Mb), explaining 11-15% of the variation, depending on the environment. One candidate gene identified in this region, Zm00001eb308070, is related to the abscisic acid pathway involving in cell death. Genomic predictions were applied to genome-wide markers (39,611 markers) contrasted with a marker subset (51 markers). Population structure explained more variation than environment in genomic prediction, but other substantial genetic background effects were additionally detected. Subset markers explained substantially less genetic variation (24.9%) for the lesion mimic than whole genome markers (55.4%) in the model, yet predicted the lesion mimic better (0.56-0.66 vs. 0.26-0.29). These results indicate this lesion mimic phenotype was less affected by environment than by epistasis and genetic background effects, which explain its transgressive segregation.
Assuntos
Estudo de Associação Genômica Ampla , Zea mays , Zea mays/genética , Epistasia Genética , Mapeamento Cromossômico , Fenótipo , Patrimônio Genético , Polimorfismo de Nucleotídeo ÚnicoRESUMO
More than 3 years have passed since Coronavirus disease 2019 (COVID-19) was declared a global pandemic, yet COVID-19 still severely impacts immunocompromised individuals including those treated with hematopoietic cell transplantation (HCT) and chimeric antigen receptor-T-cell therapies who remain at high risk for severe COVID-19 and mortality. Despite vaccination efforts, these patients have inadequate responses due to immunosuppression, which underscores the need for additional preventive approaches. The optimal timing, schedule of vaccination, and immunological correlates for protective immunity remain unknown. Antiviral therapies used early during disease can reduce mortality and severity due to COVID-19. The combination or sequential use of antivirals could be beneficial to control replication and prevent the development of treatment-related mutations in protracted COVID-19. Despite conflicting data, COVID-19 convalescent plasma remains an option in immunocompromised patients with mild-to-moderate disease to prevent progression. Protracted COVID-19 has been increasingly recognized among these patients and has been implicated in intra-host emergence of SARS-CoV-2 variants. Finally, novel SARS-CoV2-specific T-cells and natural killer cell-boosting (or -containing) products may be active against multiple variants and are promising therapies in immunocompromised patients.
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COVID-19 , Transplante de Células-Tronco Hematopoéticas , Receptores de Antígenos Quiméricos , Humanos , COVID-19/terapia , SARS-CoV-2 , Soroterapia para COVID-19 , RNA Viral , Receptores de Antígenos Quiméricos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
BACKGROUND: Chimeric antigen receptor (CAR)-T-cell therapies have revolutionized the management of acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma but come at the price of unique toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and long-term "on-target off-tumor" effects. METHODS: All of these factors increase infection risk in an already highly immunocompromised patient population. Indeed, infectious complications represent the key determinant of non-relapse mortality after CAR-T cells. The temporal distribution of these risk factors shapes different infection patterns early versus late post-CAR-T-cell infusion. Furthermore, due to the expression of their targets on B lineage cells at different stages of differentiation, CD19, and B-cell maturation antigen (BCMA) CAR-T cells induce distinct immune deficits that could require different prevention strategies. Infection incidence is the highest during the first month post-infusion and subsequently decreases thereafter. However, infections remain relatively common even a year after infusion. RESULTS: Bacterial infections predominate early after CD19, while a more equal distribution between bacterial and viral causes is seen after BCMA CAR-T-cell therapy, and fungal infections are universally rare. Cytomegalovirus (CMV) and other herpesviruses are increasingly breported, but whether routine monitoring is warranted for all, or a subgroup of patients, remains to be determined. Clinical practices vary substantially between centers, and many areas of uncertainty remain, including CMV monitoring, antibacterial and antifungal prophylaxis and duration, use of immunoglobulin replacement therapy, and timing of vaccination. CONCLUSION: Risk stratification tools are available and may help distinguish between infectious and non-infectious causes of fever post-infusion and predict severe infections. These tools need prospective validation, and their integration in clinical practice needs to be systematically studied.
Assuntos
Infecções por Citomegalovirus , Neoplasias Hematológicas , Receptores de Antígenos Quiméricos , Humanos , Antígeno de Maturação de Linfócitos B , Neoplasias Hematológicas/terapia , Terapia Baseada em Transplante de Células e TecidosRESUMO
Next-generation sequencing technologies allowed sequencing of thousands of genomes. However, there are genomic regions that remain difficult to characterize, including telomeres, centromeres, and other low-complexity regions, as well as transposable elements and endogenous viruses. Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) are closely related viruses that infect most humans and can integrate their genomes into the telomeres of infected cells. Integration also occurs in germ cells, meaning that the virus can be inherited and result in individuals harboring the virus in every cell of their body. The integrated virus can reactivate and cause disease in humans. While it is well established that the virus resides in the telomere region, the integration locus is poorly defined due to the low sequence complexity (TTAGGG)n of telomeres that cannot be easily resolved through sequencing. We therefore employed genome imaging of the integrated HHV-6A and HHV-6B genomes using whole-genome optical site mapping technology. Using this technology, we identified which chromosome arm harbors the virus genome and obtained a high-resolution map of the integration loci of multiple patients. Surprisingly, this revealed long telomere sequences at the virus-subtelomere junction that were previously missed using PCR-based approaches. Contrary to what was previously thought, our technique revealed that the telomere lengths of chromosomes harboring the integrated virus genome were comparable to the other chromosomes. Taken together, our data shed light on the genetic structure of the HHV-6A and HHV-6B integration locus, demonstrating the utility of optical mapping for the analysis of genomic regions that are difficult to sequence.
Assuntos
Herpesvirus Humano 6/fisiologia , Imagem Óptica , Telômero/metabolismo , Cromossomos Humanos/genética , Genoma Viral , Herpesvirus Humano 6/genética , Interações Hospedeiro-Patógeno , Humanos , Homeostase do TelômeroRESUMO
Human herpesvirus 6A and 6B (HHV-6) can integrate into the germline, and as a result, â¼70 million people harbor the genome of one of these viruses in every cell of their body. Until now, it has been largely unknown if 1) these integrations are ancient, 2) if they still occur, and 3) whether circulating virus strains differ from integrated ones. Here, we used next-generation sequencing and mining of public human genome data sets to generate the largest and most diverse collection of circulating and integrated HHV-6 genomes studied to date. In genomes of geographically dispersed, only distantly related people, we identified clades of integrated viruses that originated from a single ancestral event, confirming this with fluorescent in situ hybridization to directly observe the integration locus. In contrast to HHV-6B, circulating and integrated HHV-6A sequences form distinct clades, arguing against ongoing integration of circulating HHV-6A or "reactivation" of integrated HHV-6A. Taken together, our study provides the first comprehensive picture of the evolution of HHV-6, and reveals that integration of heritable HHV-6 has occurred since the time of, if not before, human migrations out of Africa.
Assuntos
Herpesvirus Humano 6/genética , Migração Humana , Filogenia , África , Humanos , FilogeografiaRESUMO
Prior reports evaluating SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia (CLL) used semiquantitative measurements of anti-S to evaluate immunity; however, neutralization assays were used to assess functional immunity in the trials leading to vaccine approval. Here, we identified decreased rates of seroconversion in vaccinated CLL patients and lower anti-S levels compared to healthy controls. Notably, we demonstrated similar results with the Roche anti-S assay and neutralization activity. Durable responses were seen at six months; augmentation with boosters was possible in responding patients. Absence of normal B cells, frequently seen in patients receiving Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors, was a strong predictor of lack of seroconversion.
Assuntos
COVID-19 , Leucemia Linfocítica Crônica de Células B , COVID-19/prevenção & controle , Vacinas contra COVID-19/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/terapia , SARS-CoV-2 , Eficácia de VacinasRESUMO
BACKGROUND: For locally advanced esophageal squamous cell carcinoma (ESCC), chemoradiation (ChemoRT) followed by surgery offers the best chance of cure, with a 35-50% pathologic complete response (pCR) rate. Given the morbidity of esophagectomy and the possibility of pCR with ChemoRT, a 'watch and wait' strategy has been proposed, particularly for squamous cell carcinoma. The ability to accurately predict which patients will have pCR from ChemoRT is critical in treatment decision making. This study assessed positron emission tomography (PET) in predicting pCR after neoadjuvant ChemoRT for ESCC. METHODS: ESCC patients treated with ChemoRT followed by surgery were identified. Maximum standard uptake value (SUV), metabolic tumor volume, total lesion glycolysis, and first-order textual features of standard deviation, kurtosis and skewness were measured from PET. Univariable and multivariable generalized linear method analyses were performed. A metabolic complete response (mCR) was defined as a post-therapy PET scan with maximum SUV < 4.0. RESULTS: Twenty-seven patients underwent ChemoRT followed by surgery, with overall pCR seen in 11 (41%) patients and radiographic mCR seen in 12 (44%) patients. Final pathology for these 12 patients revealed pCR (ypT0N0M0) in 5 (42%) patients and persistent disease in 7 (58%) patients. Univariate analysis did not reveal PET parameters predictive of pCR. CONCLUSION: Treatment of ESCC with ChemoRT often results in a robust clinical response. Among patients with an mCR after ChemoRT, disease persistence was found in 58%. The inability of PET to predict pCR is important in the context of a 'watch and wait' strategy for ESCC treated with ChemoRT.