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Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3-5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6-8 and may influence the design and production of autologous and allogeneic cell therapies.
Assuntos
Linfócitos T CD4-Positivos , Herpesvirus Humano 6 , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Ativação Viral , Latência Viral , Humanos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Ensaios Clínicos como Assunto , Regulação Viral da Expressão Gênica , Genômica , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/isolamento & purificação , Herpesvirus Humano 6/fisiologia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Encefalite Infecciosa/complicações , Encefalite Infecciosa/virologia , Receptores de Antígenos Quiméricos/imunologia , Infecções por Roseolovirus/complicações , Infecções por Roseolovirus/virologia , Análise da Expressão Gênica de Célula Única , Carga ViralRESUMO
Characterizing cell-cell communication and tracking its variability over time are crucial for understanding the coordination of biological processes mediating normal development, disease progression, and responses to perturbations such as therapies. Existing tools fail to capture time-dependent intercellular interactions and primarily rely on databases compiled from limited contexts. We introduce DIISCO, a Bayesian framework designed to characterize the temporal dynamics of cellular interactions using single-cell RNA-sequencing data from multiple time points. Our method utilizes structured Gaussian process regression to unveil time-resolved interactions among diverse cell types according to their coevolution and incorporates prior knowledge of receptor-ligand complexes. We show the interpretability of DIISCO in simulated data and new data collected from T cells cocultured with lymphoma cells, demonstrating its potential to uncover dynamic cell-cell cross talk.
Assuntos
Teorema de Bayes , Comunicação Celular , Análise de Célula Única , Análise de Célula Única/métodos , Humanos , Linfócitos T/metabolismo , Análise de Sequência de RNA/métodosRESUMO
Engineered cellular therapy with CD19-targeting chimeric antigen receptor T-cells (CAR-T) has revolutionized outcomes for patients with relapsed/refractory Large B-Cell Lymphoma (LBCL), but the cellular and molecular features associated with response remain largely unresolved. We analyzed serial peripheral blood samples ranging from day of apheresis (day -28/baseline) to 28 days after CAR-T infusion from 50 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) by integrating single cell RNA and TCR sequencing (scRNA-seq/scTCR-seq), flow cytometry, and mass cytometry (CyTOF) to characterize features associated with response to CAR-T. Pretreatment patient characteristics associated with response included presence of B cells and increased lymphocyte-to-monocyte ratio (ALC/AMC). Infusion products from responders were enriched for clonally expanded, highly activated CD8+ T cells. We expanded these observations to 99 patients from the ZUMA-1 cohort and identified a subset of patients with elevated baseline B cells, 80% of whom were complete responders. We integrated B cell proportion ï³0.5% and ALC/AMC ï³1.2 into a two-factor predictive model and applied this model to the ZUMA-1 cohort. Estimated progression free survival (PFS) at 1 year in patients meeting one or both criteria was 65% versus 31% for patients meeting neither criterion. Our results suggest that patients' immunologic state at baseline affects likelihood of response to CAR-T through both modulation of the T cell apheresis product composition and promoting a more favorable circulating immune compartment prior to therapy. These baseline immunologic features, measured readily in the clinical setting prior to CAR-T, can be applied to predict response to therapy.
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Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and costimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/imunologia , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Animais , Autofagia/imunologia , Proteínas Relacionadas à Autofagia , Antígeno B7-1/biossíntese , Antígeno B7-2/biossíntese , Antígenos CD40/biossíntese , Proteínas de Transporte/genética , Proliferação de Células , Células Cultivadas , Colite/imunologia , Cisteína Endopeptidases/biossíntese , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Transplante de Células-Tronco Hematopoéticas , Proteínas de Homeodomínio/genética , Proteínas Imediatamente Precoces/biossíntese , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Ativação Linfocitária/imunologia , Lisossomos/patologia , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Transplante Homólogo , Proteína 3 Induzida por Fator de Necrose Tumoral alfaRESUMO
The success of Mycobacterium tuberculosis (Mtb) as a pathogen rests upon its ability to grow intracellularly in macrophages. Interferon-gamma (IFN-γ) is critical in host defense against Mtb and stimulates macrophage clearance of Mtb through an autophagy pathway. Here we show that the host protein ubiquilin 1 (UBQLN1) promotes IFN-γ-mediated autophagic clearance of Mtb. Ubiquilin family members have previously been shown to recognize proteins that aggregate in neurodegenerative disorders. We find that UBQLN1 can interact with Mtb surface proteins and associates with the bacilli in vitro. In IFN-γ activated macrophages, UBQLN1 co-localizes with Mtb and promotes the anti-mycobacterial activity of IFN-γ. The association of UBQLN1 with Mtb depends upon the secreted bacterial protein, EsxA, which is involved in permeabilizing host phagosomes. In autophagy-deficient macrophages, UBQLN1 accumulates around Mtb, consistent with the idea that it marks bacilli that traffic through the autophagy pathway. Moreover, UBQLN1 promotes ubiquitin, p62, and LC3 accumulation around Mtb, acting independently of the E3 ligase parkin. In summary, we propose a model in which UBQLN1 recognizes Mtb and in turn recruits the autophagy machinery thereby promoting intracellular control of Mtb. Thus, polymorphisms in ubiquilins, which are known to influence susceptibility to neurodegenerative illnesses, might also play a role in host defense against Mtb.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Interferon gama/metabolismo , Macrófagos/metabolismo , Mycobacterium tuberculosis/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia , Camundongos , Fagossomos/metabolismoRESUMO
Mutations that alter virulence and antibiotic susceptibility arise and persist during Staphylococcus aureus bacteremia. However, an experimental system demonstrating transmission following bacteremia has been lacking, and thus implications of within-host adaptation for between-host transmission are unknown. We report that S. aureus disseminates to the gastrointestinal tract of mice following intravenous injection and readily transmits to cohoused naive mice. Both intestinal dissemination and transmission were linked to the production of virulence factors based on gene deletion studies of the sae and agr two-component systems. Furthermore, antimicrobial selection for antibiotic-resistant S. aureus displaced susceptible S. aureus from the intestine of infected hosts, which led to the preferential transmission and dominance of antibiotic-resistant bacteria among cohoused untreated mice. These findings establish an animal model to investigate gastrointestinal dissemination and transmission of S. aureus and suggest that adaptation during the course of systemic infection has implications beyond the level of a single host.
Assuntos
Bacteriemia/microbiologia , Bacteriemia/transmissão , Trato Gastrointestinal/microbiologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/transmissão , Staphylococcus aureus/isolamento & purificação , Animais , Farmacorresistência Bacteriana , Feminino , Deleção de Genes , Humanos , Camundongos Endogâmicos C57BL , Seleção Genética , Fatores de Virulência/genéticaRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many hematologic malignancies as well as non-malignant conditions. Part of the curative basis underlying HSCT for hematologic malignancies relies upon induction of the graft versus leukemia (GVL) effect in which donor immune cells recognize and eliminate residual malignant cells within the recipient, thereby maintaining remission. GVL is a clinically evident phenomenon; however, specific cell types responsible for inducing this effect and molecular mechanisms involved remain largely undefined. One of the best examples of GVL is observed after donor lymphocyte infusions (DLI), an established therapy for relapsed disease or incipient/anticipated relapse. DLI involves infusion of peripheral blood lymphocytes from the original HSCT donor into the recipient. Sustained remission can be observed in 20-80% of patients treated with DLI depending upon the underlying disease and the intrinsic burden of targeted cells. In this review, we will discuss current knowledge about mechanisms of GVL after DLI, experimental strategies for augmenting GVL by manipulation of DLI (e.g. neoantigen vaccination, specific cell type selection/depletion) and research outlook for improving DLI and cellular immunotherapies for hematologic malignancies through better molecular definition of the GVL effect.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Leucemia , Humanos , Transplante Homólogo , Transfusão de Linfócitos , Neoplasias Hematológicas/terapia , Linfócitos/patologia , Leucemia/terapiaRESUMO
Single-cell transcriptomics has become the definitive method for classifying cell types and states, and can be augmented with genotype information to improve cell lineage identification. Due to constraints of short-read sequencing, current methods to detect natural genetic barcodes often require cumbersome primer panels and early commitment to targets. Here we devise a flexible long-read sequencing workflow and analysis pipeline, termed nanoranger, that starts from intermediate single-cell cDNA libraries to detect cell lineage-defining features, including single-nucleotide variants, fusion genes, isoforms, sequences of chimeric antigen and TCRs. Through systematic analysis of these classes of natural 'barcodes', we define the optimal targets for nanoranger, namely those loci close to the 5' end of highly expressed genes with transcript lengths shorter than 4 kB. As proof-of-concept, we apply nanoranger to longitudinal tracking of subclones of acute myeloid leukemia (AML) and describe the heterogeneous isoform landscape of thousands of marrow-infiltrating immune cells. We propose that enhanced cellular genotyping using nanoranger can improve the tracking of single-cell tumor and immune cell co-evolution.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda , Humanos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Fenótipo , Perfilação da Expressão Gênica/métodosRESUMO
Combined tracking of clonal evolution and chimeric cell phenotypes could enable detection of the key cellular populations associated with response following therapy, including after allogeneic hematopoietic stem cell transplantation (HSCT). We demonstrate that mitochondrial DNA (mtDNA) mutations co-evolve with somatic nuclear DNA mutations at relapse post-HSCT and provide a sensitive means to monitor these cellular populations. Further, detection of mtDNA mutations via single-cell ATAC with select antigen profiling by sequencing (ASAP-seq) simultaneously determines not only donor and recipient cells, but also their phenotype, at frequencies of 0.1-1%. Finally, integration of mtDNA mutations, surface markers, and chromatin accessibility profiles enables the phenotypic resolution of leukemic populations from normal immune cells, thereby providing fresh insights into residual donor-derived engraftment and short-term clonal evolution following therapy for post-transplant leukemia relapse. As throughput evolves, we envision future development of single-cell sequencing-based post-transplant monitoring as a powerful approach for guiding clinical decision making.
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Understanding how intra-tumoral immune populations coordinate to generate anti-tumor responses following therapy can guide precise treatment prioritization. We performed systematic dissection of an established adoptive cellular therapy, donor lymphocyte infusion (DLI), by analyzing 348,905 single-cell transcriptomes from 74 longitudinal bone-marrow samples of 25 patients with relapsed myeloid leukemia; a subset was evaluated by protein-based spatial analysis. In acute myelogenous leukemia (AML) responders, diverse immune cell types within the bone-marrow microenvironment (BME) were predicted to interact with a clonally expanded population of ZNF683 + GZMB + CD8+ cytotoxic T lymphocytes (CTLs) which demonstrated in vitro specificity for autologous leukemia. This population, originating predominantly from the DLI product, expanded concurrently with NK and B cells. AML nonresponder BME revealed a paucity of crosstalk and elevated TIGIT expression in CD8+ CTLs. Our study highlights recipient BME differences as a key determinant of effective anti-leukemia response and opens new opportunities to modulate cell-based leukemia-directed therapy.
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INTRODUCTION: The curative basis of allogeneic hematopoietic stem cell transplantation (HSCT) relies in part upon the graft versus leukemia (GvL) effect, whereby donor immune cells recognize and eliminate recipient malignant cells. However, alloreactivity of donor cells against recipient tissues may also be deleterious. Chronic graft versus host disease (cGvHD) is an immunologic phenomenon wherein alloreactive donor T cells aberrantly react against host tissues, leading to damaging inflammatory symptoms. AREAS COVERED: Here, we discuss biological insights into GvL and cGvHD and strategies to balance the prevention of GvHD with maintenance of GvL in modern HSCT. EXPERT OPINION/COMMENTARY: Relapse remains the leading cause of mortality after HSCT with rates as high as 40% for some diseases. GvHD is a major cause of morbidity after HSCT, occurring in up to half of patients and responsible for 15-20% of deaths after HSCT. Intriguingly, the development of chronic GvHD may be linked to lower relapse rates after HSCT, suggesting that GvL and GvHD may be complementary sides of the immunologic foundation of HSCT. The ability to fine tune the balance of GvL and GvHD will lead to improvements in survival, relapse rates, and quality of life for patients undergoing HSCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia , Humanos , Qualidade de Vida , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia/terapia , Doença Crônica , RecidivaRESUMO
Characterizing cell-cell communication and tracking its variability over time is essential for understanding the coordination of biological processes mediating normal development, progression of disease, or responses to perturbations such as therapies. Existing tools lack the ability to capture time-dependent intercellular interactions, such as those influenced by therapy, and primarily rely on existing databases compiled from limited contexts. We present DIISCO, a Bayesian framework for characterizing the temporal dynamics of cellular interactions using single-cell RNA-sequencing data from multiple time points. Our method uses structured Gaussian process regression to unveil time-resolved interactions among diverse cell types according to their co-evolution and incorporates prior knowledge of receptor-ligand complexes. We show the interpretability of DIISCO in simulated data and new data collected from CAR-T cells co-cultured with lymphoma cells, demonstrating its potential to uncover dynamic cell-cell crosstalk.
RESUMO
The ability of posttransplant cyclophosphamide (PTCY) to facilitate haploidentical transplantation has spurred interest in whether PTCY can improve clinical outcomes in patients with HLA-matched unrelated donors undergoing peripheral blood stem cell transplantation (PBSCT). We investigated our institutional experience using PTCY-based graft-versus-host disease (GVHD) prophylaxis compared with conventional tacrolimus-based regimens. We compared overall survival, progression-free survival (PFS), relapse, nonrelapse mortality, and acute and chronic GVHD in 107 adult patients receiving a PTCY-based regimen vs 463 patients receiving tacrolimus-based regimens for GVHD prophylaxis. The 2 cohorts were well balanced for baseline characteristics except that more patients in the PTCY cohort having received 7-of-8-matched PBSCT. There was no difference in acute GVHD. All-grade chronic GVHD and moderate-to-severe chronic GVHD were substantially reduced in patients receiving PTCY compared with in those receiving tacrolimus-based regimens (2-year moderate-to-severe chronic GVHD: 12% vs 36%; P < .0001). Recipients of PTCY-based regimens also had a lower incidence of relapse compared with recipients of tacrolimus-based regimens (25% vs 34% at 2-years; P = .027), primarily in patients who received reduced intensity conditioning. This led to improved PFS in the PTCY cohort (64% vs 54% at 2 years; P = .02). In multivariable analysis, the hazard ratio was 0.59 (P = .015) for PFS and the subdistribution hazard ratio was 0.27 (P < .0001) for moderate-to-severe chronic GVHD and 0.59 (P = .015) for relapse. Our results suggest that PTCY prophylaxis is associated with lower rates of relapse and chronic GVHD in patients who receive HLA-matched unrelated donor PBSCT.
Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Tacrolimo/uso terapêutico , Incidência , Transplante de Células-Tronco Hematopoéticas/métodos , Doadores não Relacionados , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Ciclofosfamida/uso terapêutico , RecidivaRESUMO
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells among nonresponders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-T regulatory cells to drive relapse.
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Produtos Biológicos , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Antígenos CD19 , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucócitos Mononucleares , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores de Antígenos Quiméricos/genéticaRESUMO
The year 2020 marked the 30th anniversary of the Nobel Prize in Medicine awarded to E. Donnall Thomas for the development of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat hematologic malignancies and other blood disorders. Dr. Thomas, "father of bone marrow transplantation," first developed and reported this technique in 1957, and in the ensuing decades, this seminal study has impacted fundamental work in hematology and cancer research, including advances in hematopoiesis, stem cell biology, tumor immunology, and T-cell biology. As the first example of cancer immunotherapy, understanding the mechanisms of antitumor biology associated with allo-HSCT has given rise to many of the principles used today in the development and implementation of novel transformative immunotherapies. Here we review the historical basis underpinning the development of allo-HSCT as well as advances in knowledge obtained by defining mechanisms of allo-HSCT activity. We review how these principles have been translated to novel immunotherapies currently utilized in clinical practice and describe potential future applications for allo-HSCT in cancer research and development of novel therapeutic strategies.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia/métodos , Neoplasias/imunologia , Animais , Antineoplásicos/farmacologia , Transplante de Medula Óssea , Citocinas/metabolismo , Reação Enxerto-Hospedeiro , Antígenos HLA/imunologia , Neoplasias Hematológicas , Humanos , Sistema Imunitário , Imunofenotipagem , Camundongos , Antígenos de Histocompatibilidade Menor/imunologia , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Células-Tronco/citologia , Linfócitos T/imunologia , Transplante HomólogoRESUMO
We sought to evaluate the impact of cryopreservation of unrelated donor (URD) peripheral blood stem cell (PBSC) grafts on engraftment, chimerism, and immune reconstitution in the context of the COVID-19 pandemic. We reviewed stem cell product characteristics and clinical outcomes in 101 patients receiving cryopreserved PBSCs from URDs between January 1, 2019 and 31 December, 2020, compared with 203 patients receiving fresh URD PBSCs. We observed no differences in 6-month overall survival, progression-free survival, or nonrelapse mortality. Patients receiving cryopreserved PBSCs had delayed platelet engraftment and impaired reconstitution of white blood cells and T-cell subsets at day 30. Thirty-four percent of patients receiving cryopreserved grafts had CD3 chimerism <50% at day 30 after transplantation, compared with 14% of patients receiving fresh PBSCs (P = .0002). At day 100, this difference persisted (CD3+ chimerism <50%: 17% of cryopreserved cohort vs 6% of fresh cohort; P = .016). Greater product age at infusion was associated with increased graft failure, independent of cryopreservation. Receipt of grafts >48 hours old at time of cryopreservation or infusion significantly increased the risk of graft failure (subdistribution hazard ratio = 4.57; 95% confidence interval, 1.71-12.3; P = .0025). Our data indicate that cryopreservation is associated with similar overall short-term clinical outcomes compared with fresh PBSC. However, patients must be monitored closely for increased risk of other potentially adverse outcomes, including graft failure and poor immune recovery, particularly for grafts with older overall age at infusion. Longer-term follow-up is needed to determine impact on relapse and survival.
Assuntos
COVID-19 , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Aloenxertos , Criopreservação , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pandemias , SARS-CoV-2RESUMO
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified in late 2019 as the causative agent of COVID-19, was declared a pandemic by the World Health Organization on 11 March 2020. Widespread community transmission in the United States triggered a nationwide shutdown, raising major challenges for administration of hematopoietic stem cell transplant (HSCT) and chimeric antigen receptor (CAR)-T cell therapies, leading many centers to delay or cancel operations. We sought to assess the impact of the COVID-19 pandemic on operations and clinical outcomes for HSCT and CAR-T cellular therapies at the Dana-Farber Cancer Institute by reviewing administration and outcomes in 127 cell therapy patients treated during the initial COVID-19 surge: 62 adult allogeneic HSCT (allo-HSCT), 38 autologous HSCT (auto-HSCT), and 27 CAR-T patients. Outcomes were compared with 66 allo-HSCT, 43 auto-HSCT, and 33 CAR-T patients treated prior to the pandemic. A second control cohort was evaluated for HSCT groups to reflect seasonal variation in infections. Although there were changes in donor selection and screening as well as cryopreservation patterns of donor products, no differences were observed across groups in 100-day overall survival, progression-free survival, rates of non-COVID-19 infections, including hospital length of stay, neutrophil engraftment, graft failure, acute graft-versus-host disease in allo-HSCT patients, or cytokine release syndrome and neurotoxicity in CAR-T patients. No HSCT patients contracted COVID-19 between days 0 and 100. One CAR-T patient contracted COVID-19 at day +51 and died of the disease. Altogether, our data indicate that cellular therapies can be safely administered throughout the ongoing COVID-19 pandemic with appropriate safeguards.
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COVID-19/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Idoso , COVID-19/mortalidade , COVID-19/patologia , COVID-19/virologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunoterapia Adotiva , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , SARS-CoV-2/isolamento & purificação , Transplante Autólogo , Transplante Homólogo , Estados Unidos , Adulto JovemRESUMO
To elucidate mechanisms by which T cells eliminate leukemia, we study donor lymphocyte infusion (DLI), an established immunotherapy for relapsed leukemia. We model T cell dynamics by integrating longitudinal, multimodal data from 94,517 bone marrow-derived single T cell transcriptomes in addition to chromatin accessibility and single T cell receptor sequencing from patients undergoing DLI. We find that responsive tumors are defined by enrichment of late-differentiated T cells before DLI and rapid, durable expansion of early differentiated T cells after treatment, highly similar to "terminal" and "precursor" exhausted subsets, respectively. Resistance, in contrast, is defined by heterogeneous T cell dysfunction. Surprisingly, early differentiated T cells in responders mainly originate from pre-existing and novel clonotypes recruited to the leukemic microenvironment, rather than the infusion. Our work provides a paradigm for analyzing longitudinal single-cell profiling of scenarios beyond adoptive cell therapy and introduces Symphony, a Bayesian approach to infer regulatory circuitry underlying T cell subsets, with broad relevance to exhaustion antagonists across cancers.