RESUMO
INTRODUCTION: While CAR T-cell therapy has led to remarkable responses in relapsed B-cell hematologic malignancies, only 50% of patients ultimately have a complete, sustained response. Understanding the mechanisms of resistance and relapse after CAR T-cell therapy is crucial to future development and improving outcomes. AREAS COVERED: We review reasons for both primary resistance and relapse after CAR T-cell therapies. Reasons for primary failure include CAR T-cell manufacturing problems, suboptimal fitness of autologous T-cells themselves, and intrinsic features of the underlying cancer and tumor microenvironment. Relapse after initial response to CAR T-cell therapy may be antigen-positive, due to CAR T-cell exhaustion or limited persistence, or antigen-negative, due to antigen-modulation on the target cells. Finally, we discuss ongoing efforts to overcome resistance to CAR T-cell therapy with enhanced CAR constructs, manufacturing methods, alternate cell types, combinatorial strategies, and optimization of both pre-infusion conditioning regimens and post-infusion consolidative strategies. EXPERT OPINION: There is a continued need for novel approaches to CAR T-cell therapy for both hematologic and solid malignancies to obtain sustained remissions. Opportunities for improvement include development of new targets, optimally combining existing CAR T-cell therapies, and defining the role for adjunctive immune modulators and stem cell transplant in enhancing long-term survival.
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Neoplasias Hematológicas , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Linfócitos T , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Linfócitos T/imunologia , Recidiva , Animais , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Chimeric antigen receptor (CAR) T-cells have demonstrated significant efficacy in targeting hematological malignancies, and their use continues to expand. Despite substantial efforts spent on the optimization of protocols for CAR T-cell manufacturing, critical parameters of cell culture such as pH or oxygenation are rarely actively monitored during cGMP CAR T-cell generation. A comprehensive understanding of the role that these factors play in manufacturing may help in optimizing patient-specific CAR T-cell therapy with maximum benefits and minimal toxicity. METHODS: This retrospective study examined cell culture supernatants from the manufacture of CAR T-cells for 20 patients with B-cell malignancies enrolled in a phase 1/2 clinical trial of anti-CD22 CAR T-cells. MetaFLEX was used to measure supernatant pH, oxygenation, and metabolites, and a Bio-Plex assay was used to assess protein levels. Correlations were assessed between the pH of cell culture media throughout manufacturing and cell proliferation as well as clinical outcomes. Next-generation sequencing was conducted to examine gene expression profiles of the final CAR T-cell products. RESULTS: A pH level at the lower range of normal at the beginning of the manufacturing process significantly correlated with measures of T-cell expansion and metabolism. Stable or rising pH during the manufacturing process was associated with clinical response, whereas a drop in pH was associated with non-response. CONCLUSIONS: pH has potential to serve as an informative factor in predicting CAR T-cell quality and clinical outcomes. Thus, its active monitoring during manufacturing may ensure a more effective CAR T-cell product.
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Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Linfócitos T , Humanos , Concentração de Íons de Hidrogênio , Linfócitos T/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Proliferação de Células , Técnicas de Cultura de CélulasRESUMO
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of hematologic malignancies and holds promise for solid tumors. While responses to CAR T-cell therapy have surpassed other available options for patients with refractory malignancies, not all patients respond the same way. The reason for this variability is not currently understood. Therefore, there is a strong need to identify characteristics of patients as well as cellular products that lead to an effective response to CAR T-cell therapy. CONTENT: In this review, we discuss potential biomarkers that may predict clinical outcomes of CAR T-cell therapy. Based on correlative findings from clinical trials of both commercially available and early-phase products, we classify biomarkers into categories of pre- and post-infusion as well as patient and product-related markers. Among the biomarkers that have been explored, measures of disease burden both pre- and post-infusion, as well as CAR T-cell persistence post-infusion, are repeatedly identified as predictors of disease response. Higher proportions of early memory T cells at infusion appear to be favorable, and tracking T-cell subsets throughout treatment will likely be critical. SUMMARY: There are a growing number of promising biomarkers of CAR T-cell efficacy described in the research setting, however, none of these have been validated for clinical use. Some potentially important predictors of response may be difficult to obtain routinely under the current CAR T-cell therapy workflow. A collaborative approach is needed to select biomarkers that can be validated in large cohorts and incorporated into clinical practice.
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Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/genética , Biomarcadores , Efeitos Psicossociais da Doença , Terapia Baseada em Transplante de Células e TecidosRESUMO
Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs. Primary objectives included characterizing the incidence, outcomes, and preinfusion factors associated with HLH-LTs. Among 185 CAYAs infused with tisagenlecleucel, 26 (14.1%) met the criteria for HLH-LTs. One-year overall survival and relapse-free survival were 25.7% and 4.7%, respectively, in those with HLH-LTs compared with 80.1% and 57.6%, respectively, in those without. In multivariable analysis for death, meeting criteria for HLH-LTs carried a hazard ratio of 4.61 (95% confidence interval, 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-LTs had higher pretisagenlecleucel disease burden, ferritin, and C-reactive protein levels and lower platelet and absolute neutrophil counts than patients with HG- or NLG-CRS without HLH-LTs. Overall, CAYAs with B-ALL who developed HLH-LTs after tisagenlecleucel experienced high rates of relapse and nonrelapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-LTs after tisagenlecleucel.
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Linfoma de Burkitt , Linfo-Histiocitose Hemofagocítica , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores de Antígenos Quiméricos , Humanos , Criança , Adulto Jovem , Linfo-Histiocitose Hemofagocítica/etiologia , Estudos Retrospectivos , Receptores de Antígenos de Linfócitos T , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Linfoma de Burkitt/complicações , Doença CrônicaRESUMO
Cryopreservation of chimeric antigen receptor (CAR) T cells facilitates shipment, timing of infusions, and storage of subsequent doses. However, reports on the impact of cryopreservation on CAR T cell efficacy have been mixed. We retrospectively compared clinical outcomes between patients who received cryopreserved versus fresh CAR T cells for treatment of B cell leukemia across two cohorts of pediatric and young adult patients: those who received anti-CD22 CAR T cells and those who received bispecific anti-CD19/22 CAR T cells. Manufacturing methods were consistent within each trial but differed between the two trials, allowing for exploration of cryopreservation within different manufacturing platforms. Among 40 patients who received anti-CD22 CAR T cells (21 cryopreserved cells and 19 fresh), there were no differences in in vivo expansion, persistence, incidence of toxicities, or disease response between groups with cryopreserved and fresh CAR T cells. Among 19 patients who received anti-CD19/22 CAR T cells (11 cryopreserved and 8 fresh), patients with cryopreserved cells had similar expansion, toxicity incidence, and disease response, with decreased CAR T cell persistence. Overall, our data demonstrate efficacy of cryopreserved CAR T cells as comparable to fresh infusions, supporting cryopreservation, which will be crucial for advancing the field of cell therapy.
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Proteína Antagonista do Receptor de Interleucina 1 , Leucemia-Linfoma Linfoblástico de Células Precursoras , Administração Intravenosa , Criança , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T , Adulto JovemRESUMO
AIM: We aimed to describe changes in invasive pneumococcal disease (IPD) hospitalisations after introduction of the pneumococcal conjugate vaccine (PCV13). METHODS: This was a retrospective analysis of the Pediatric Health Information System (PHIS) database, including children with IPD pre-PCV13 (2004-2009) and post-PCV13 (2012-2017). Healthy children and those with chronic conditions were analysed separately. The primary outcome was IPD incidence. Secondary outcomes included length of stay, intensive care unit (ICU) admission, mechanical ventilation and mortality. RESULTS: 9160 hospitalisations for IPD were included. The IPD rate per 100 000 discharges was 180 pre-PVC13 and 150 post-PCV13 [17% decrease (P = 0.085)]. The observed IPD rate in 2017 was 45.5% lower than the rate predicted by the pre-PCV13 trend (95% CI: 44%-46%). While a significant decrease in IPD (32%, P = 0.026) was observed among healthy children, there was no change in those with chronic conditions (9%, P = 0.24). In the post-PCV13 period, more IPD patients had chronic conditions, ICU admissions and longer ICU stays. CONCLUSION: Although there was no overall reduction in IPD after PCV13, we observed a significant decrease in IPD among healthy patients. Further research is needed to elucidate microbiology or other factors contributing to persistent IPD hospitalisations.
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Criança Hospitalizada , Infecções Pneumocócicas , Criança , Humanos , Incidência , Lactente , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Estudos RetrospectivosRESUMO
There are nearly 70,000 new cancer diagnoses made annually in adolescents and young adults (AYAs) in the United States. Historically, AYA patients with cancer, aged 15 to 39 years, have not shown the same improved survival as older or younger cohorts. This article reviews the contemporary cancer incidence and survival data through 2015 for the AYA patient population based on the National Cancer Institute's Surveillance, Epidemiology, and End Results registry program and the North American Association of Central Cancer Registries. Mortality data through 2016 from the Centers for Disease Control and Prevention's National Center for Health Statistics are also described. Encouragingly, absolute and relative increases in 5-year survival for AYA cancers have paralleled those of childhood cancers since the year 2000. There has been increasing attention to these vulnerable patients and improved partnerships and collaboration between adult and pediatric oncology; however, obstacles to the care of this population still occur at multiple levels. These vulnerabilities fall into 3 significant categories: research efforts and trial enrollment directed toward AYA malignancies, access to care and insurance coverage, and AYA-specific psychosocial support. It is critical for providers and health care delivery systems to recognize that the AYA population remains vulnerable to provider and societal complacency.
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Oncologia/tendências , Neoplasias/epidemiologia , Adolescente , Adulto , Fatores Etários , Humanos , Incidência , Oncologia/métodos , Neoplasias/psicologia , Neoplasias/terapia , Programa de SEER , Taxa de Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Aerosolized ribavirin has been used in pediatric immunocompromised patients to treat acute respiratory viral infections, but oral ribavirin may be a less expensive alternative that allows for outpatient therapy. Oral ribavirin has compared favorably to aerosolized ribavirin in adult studies, but data on safety are lacking in pediatric populations. Four cases are described in which oral ribavirin was used to treat viral respiratory infections in recipients of allogeneic hematopoietic stem cell transplants at a Children's Hospital, demonstrating safety and feasibility.
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Alemtuzumab/efeitos adversos , Antivirais/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/efeitos adversos , Infecções por Paramyxoviridae/tratamento farmacológico , Ribavirina/administração & dosagem , Condicionamento Pré-Transplante/efeitos adversos , Administração Oral , Alemtuzumab/uso terapêutico , Antivirais/uso terapêutico , Criança , Quimioterapia Combinada , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Lactente , Masculino , Infecções por Paramyxoviridae/imunologia , Ribavirina/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adulto JovemRESUMO
OBJECTIVES: To improve the recognition of differences in presentation amongst patients with type 1 laryngeal clefts of various ages and better understand the age dependent outcomes of injection laryngoplasty. A second aim was to analyze the discrepancies between swallow assessment modalities in various age groups with type I laryngeal clefts undergoing injection laryngoplasty. METHODS: A retrospective review of electronic medical records of patients who underwent injection laryngoplasty from 2009 through 2015â¯at a tertiary care children's hospital. Data extracted included: Demographics, histories and physical exam findings, diagnostic studies, and medical and surgical treatments. RESULTS: Most (72/102, 70.6%) patients were male with a median gestational age at birth of 37 weeks (range 24-41 weeks). Formula thickening and GERD medications were used in 94/102 (92.2%) and 97/102 (95.1%) patients, respectively. Comorbid GERD, laryngomalacia, tracheomalacia, and subglottic stenosis were present in 98/102 (96.1%), 40/102 (39.2%), 9/102 (8.8%), and 14/102 (13.7%) patients, respectively. There was no significant difference in demographics, comorbidities or medical therapy between age groups. Symptoms at presentation differed between age groups with stridor (χ2(1)â¯=â¯11.6, pâ¯=â¯0.002) and cyanosis (χ2(1)â¯=â¯8.13, pâ¯=â¯0.012) being more common in the 0-3-month group compared to the 12-36 month group. Symptom resolution and the odds of undergoing additional surgery (second injection or suture repair) over time, however, did not differ. There was a significant reduction in aspiration with thins during FEES (McNemar χ2(1)â¯=â¯10.7, pâ¯=â¯0.002) and aspiration with nectar during MBS (McNemar χ2(1)â¯=â¯5.26, pâ¯=â¯0.035) post-injection. After injection, there was significant agreement in aspiration with thins between FEES and MBS (kappaâ¯=â¯0.308⯱â¯SE 0.170, pâ¯=â¯0.035). However, finding aspiration with thins was more common during MBS than during FEES (McNemar χ2(1)â¯=â¯7.00, pâ¯=â¯0.016). There were no differences in swallow evaluation findings between the age groups. CONCLUSIONS: Symptoms of type I laryngeal clefts may differ by age. However, there was no impact of age on the safety and efficacy of surgical intervention.
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Anormalidades Congênitas/cirurgia , Transtornos de Deglutição/cirurgia , Deglutição , Laringoplastia/métodos , Laringe/anormalidades , Fatores Etários , Sulfato de Bário , Pré-Escolar , Anormalidades Congênitas/fisiopatologia , Meios de Contraste , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Endoscopia Gastrointestinal , Feminino , Humanos , Lactente , Recém-Nascido , Injeções , Laringe/fisiopatologia , Laringe/cirurgia , Masculino , Reoperação , Aspiração Respiratória/etiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS: Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS: Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48µM (normal 30-119µM) to 854±25µM (treatment goal ≤360µM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900µM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS: Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY: Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.
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Rejeição de Enxerto , Hepatócitos/transplante , Fígado/efeitos da radiação , Condicionamento Pré-Transplante , Adulto , Animais , Feminino , Humanos , Hepatopatias/terapia , Macaca fascicularis , Masculino , Suínos , Transplante HeterólogoRESUMO
Historically, 9-29% of pediatric liver transplant recipients have required retransplantation. Although outcomes have improved over the last decade, currently published patient and graft survival remain lower after retransplant than after primary transplant. Data from liver retransplantation recipients at our institution between 1991 and 2013 were retrospectively reviewed. Kaplan-Meier estimates were used to depict patient and graft survival. Predictors of survival were analyzed using a series of Cox proportional hazards models. Predictors were analyzed separately for patients who had "early" (≤ 30 days after primary transplant) and "late" retransplants. Eighty-four patients underwent retransplant at a median time of 241 days. Sixty percent had late retransplants. At one, five, and 10 yr, actuarial patient and graft survival were 73%/71%, 66%/63%, and 58%/53%, respectively. Since 2002, patient and graft survival improved to 86%/86% at one yr and 93%/87% at five yr. While operative complications were a common cause of death after earlier retransplants, since 2002, infection has been the only cause of death. Significant morbidities at five-yr follow-up include renal dysfunction (15%), diabetes (13%), hypertension (26%), chronic rejection (7%), and PTLD (2%). Current survival after pediatric liver retransplantation has improved significantly, but long-term immunosuppressant morbidity remains an opportunity for improvement.
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Sobrevivência de Enxerto , Transplante de Fígado/mortalidade , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Modelos de Riscos Proporcionais , Reoperação/mortalidade , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
We examined factors that affect decision-making for families presented with a phase I clinical trial of hepatocyte transplant as a potential alternative to liver transplant for their children among two groups: (i) families who were actually offered enrollment in the hepatocyte trial and; (ii) families whose children had liver transplants before the trial was available. We conducted semi-structured interviews about actual and hypothetical decision-making regarding trial participation and used grounded theory analysis to identify common themes. The most common motivator for participation was decline in the child's health. The most common deterrent was lack of data from prior hepatocyte transplants, particularly when compared with data available about liver transplant. Interviewees' point of comparison for evaluating relative benefits and risks of hepatocyte transplant oscillated between the alternative of doing nothing while waiting for a liver (the relevant alternative) vs. the alternative of getting a liver. These results suggest that families' reluctance to participate may result from misconceptions about severity of the child's disease, underestimating risks of liver transplant, or confusion about the role of hepatocyte transplant in the treatment pathway. Clarification of available treatment alternatives and associated risks as part of informed consent may improve the quality of decision-making regarding trial enrollment.
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Ensaios Clínicos como Assunto , Hepatócitos/transplante , Falência Hepática/terapia , Pais/psicologia , Participação do Paciente , Adulto , Atitude Frente a Saúde , Tomada de Decisões , Feminino , Humanos , Consentimento Livre e Esclarecido , Masculino , Educação de Pacientes como Assunto , Preferência do Paciente , Seleção de Pacientes , RiscoRESUMO
For decades, autologous ex vivo gene therapy has been postulated as a potential alternative to parenteral administration of recombinant proteins. However, achieving effective cellular engraftment of previously retrieved patient cells is challenging. Recently, our ability to engineer vasculature in vivo has allowed for the introduction of instructions into tissues by genetically modifying the vascular cells that build these blood vessels. In the present study, we genetically engineered human blood-derived endothelial colony-forming cells (ECFCs) to express erythropoietin (EPO) under the control of a tetracycline-regulated system, and generated subcutaneous vascular networks capable of systemic EPO release in immunodeficient mice. These ECFC-lined vascular networks formed functional anastomoses with the mouse vasculature, allowing direct delivery of recombinant human EPO into the bloodstream. After activation of EPO expression, erythropoiesis was induced in both normal and anemic mice, a process that was completely reversible. This approach could relieve patients from frequent EPO injections, reducing the medical costs associated with the management of anemia. We propose this ECFC-based gene-delivery strategy as a viable alternative technology when routine administration of recombinant proteins is needed.
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Anemia/terapia , Vasos Sanguíneos/fisiologia , Eritropoese/fisiologia , Eritropoetina/genética , Engenharia Genética/métodos , Terapia Genética/métodos , Anemia/etiologia , Anemia/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Eritropoetina/metabolismo , Estudos de Viabilidade , Regulação da Expressão Gênica/fisiologia , Humanos , Transplante de Células-Tronco Mesenquimais , Camundongos , Camundongos Nus , Lesões por Radiação/complicações , Insuficiência Renal/complicações , Tela Subcutânea/irrigação sanguínea , Transfecção/métodos , Transplante Autólogo , Transplante HeterólogoRESUMO
Umbilical cord blood (UCB) is recognized as an enriched source of endothelial progenitor cells (EPCs) with potential therapeutic value. Because cryopreservation is the only reliable method for long-term storage of UCB cells, the clinical application of EPCs depends on our ability to acquire them from cryopreserved samples; however, the feasibility of doing so remains unclear. In this study we demonstrate that EPCs can be isolated from cryopreserved UCB-derived mononuclear cells (MNCs). The number of outgrowth EPC colonies that emerged in culture from cryopreserved samples was similar to that obtained from fresh UCB. Furthermore, EPCs obtained from cryopreserved MNCs were phenotypically and functionally indistinguishable from freshly isolated ones, including the ability to form blood vessels in vivo. Our results eliminate the necessity of performing cell isolation procedures ahead of future clinical needs and suggest that EPCs derived from cryopreserved UCB may be suitable for EPC-related therapies.