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ABSTRACT: We show that red cell exchange (RCE) treats hyperleukocytosis in acute leukemia. RCE provided similar leukoreduction to standard therapeutic leukoreduction and could be superior in patients with severe anemia or monocytic leukemias or when requiring rapid treatment.
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Leucemia Monocítica Aguda , Leucemia Mieloide Aguda , Leucostasia , Adulto , Humanos , Leucostasia/terapia , Leucemia Mieloide Aguda/terapia , Leucemia Monocítica Aguda/terapia , Doença Aguda , Leucaférese , Leucocitose/terapiaRESUMO
The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. In the Ninth Edition, the JCA Special Issue Writing Committee has incorporated systematic review and evidence-based approaches in the grading of evidence and categorization of apheresis indications to make recommendations on the use of apheresis in a wide variety of diseases and conditions. This edition has largely maintained the general layout and concept of a fact sheet introduced in the Fourth Edition (2007). Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease or medical condition. The Ninth Edition of the JCA Special Issue comprises 91 fact sheets and 166 graded and categorized indications. This includes seven new fact sheets, nine new indications on existing fact sheets, and eight changes in the category for existing indications. The Ninth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.
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Remoção de Componentes Sanguíneos , Medicina Baseada em Evidências , Humanos , Estados Unidos , RedaçãoRESUMO
BACKGROUND AIMS: This white paper was developed to provide leukapheresis guidance for the collection of mononuclear cells from adult and pediatric patients who are destined for immune effector cell (IEC) therapies for commercial and research applications. Currently, there is considerable variability in leukapheresis processes and limited published information regarding best practices relevant to new cellular therapies, especially IECs. Herein the authors address critical leukapheresis questions in five domains to help guide consistent collection processes and ensure high-quality products. The first four domains are onboarding, pre-collection, collection and post-collection, with protocol feasibility, preparation, care and follow-up of the patient/donor at each step, respectively, and technical considerations during collection. The fifth domain of quality assurance focuses on ensuring product potency, purity, safety and auditing. METHODS: The American Society for Apheresis (ASFA) Clinical Applications Committee (IEC Therapy Subcommittee) was charged by the society's board of directors with working collaboratively with other ASFA committees and organizations, including the Foundation for the Accreditation of Cellular Therapy, Association for the Advancement of Blood and Biotherapies, American Society for Transplantation and Cellular Therapy, National Marrow Donor Program and International Society for Cell & Gene Therapy, to develop guidelines regarding leukapheresis collection of cells destined for the manufacture of IEC therapies. After a review of the literature and discussion with members of the involved committees and various institutions, a draft guidance was created and circulated for comment and revision. RESULTS: Critical aspects of apheresis that could affect the quality and quantity of the leukapheresis product were identified. These areas were then discussed and reviewed. After consensus, the best practice guidelines were proposed and accepted. CONCLUSIONS: In the current era of rapid growth of IEC therapies, it is important to address critical leukapheresis steps to provide high-quality products and more consistent practices and to eliminate redundant efforts.
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Remoção de Componentes Sanguíneos , Adulto , Remoção de Componentes Sanguíneos/métodos , Terapia Baseada em Transplante de Células e Tecidos , Criança , Consenso , Humanos , Leucaférese/métodos , Doadores de Tecidos , Estados UnidosRESUMO
BACKGROUND: Chimeric antigen receptor T (CAR-T) cell successes have encouraged continued clinical study. Apheresis collection of starting material for CAR-T cell therapy product manufacturing is critical but described approaches suggest variability and clinical guidelines are currently lacking. The goal of this study was to gather and assess variability in apheresis collection descriptions in publicly available CAR T-cell therapy clinical trials. STUDY DESIGN: We searched clinicaltrials.gov (a publicly available clinical trial database) for "chimeric antigen receptor T cells" on July 01, 2020 and studies accessed July 30, 2020-August 15, 2020. Data collected included date posted, study characteristics, apheresis mentions (number, location, and context), laboratory parameters and transfusion allowances. Apheresis context was analyzed using a qualitative inductive approach of grounded theory method with open coding. Text was classified into 37 context codes, grouped into 12 categories, and then consolidated into patient, procedure, product, and miscellaneous themes. RESULTS: Apheresis was mentioned 1044 times in 322 (51.9%) of 621 total studies. Laboratory parameters mentioned included white blood cells (100 studies), absolute neutrophil count (220 studies), absolute lymphocyte count (102 studies), CD3+ cell (38 studies), hemoglobin (233 studies, 54 studies specified transfusion allowance), and platelet (269 studies, 48 studies specified transfusion allowance). CONCLUSIONS: Apheresis collection of CAR-T cell products is not well-defined in clinical study descriptions and the context is inconsistent. Laboratory parameters useful for apheresis collection are variably present and do not consistently align with current practices. Further exploration, and clinical guideline development will encourage alignment of apheresis collections for CAR-T cell products.
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Remoção de Componentes Sanguíneos , Receptores de Antígenos Quiméricos , Remoção de Componentes Sanguíneos/métodos , Humanos , Imunoterapia Adotiva , Contagem de Linfócitos , Linfócitos TRESUMO
Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (10(5) cells/kg). At the 10(5) cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD.
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Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transfusão de Linfócitos , Subpopulações de Linfócitos T/transplante , Adulto , Anemia Refratária com Excesso de Blastos/terapia , Fator Ativador de Células B/biossíntese , Preservação de Sangue , Antígenos CD28/imunologia , Complexo CD3/imunologia , Células Cultivadas/transplante , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Criopreservação , Citocinas/análise , Relação Dose-Resposta Imunológica , Estudos de Viabilidade , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Histocompatibilidade , Humanos , Recém-Nascido , Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos/efeitos adversos , Masculino , Dose Máxima Tolerável , Proteínas de Membrana/biossíntese , Pessoa de Meia-Idade , Neutrófilos/transplante , Especificidade do Receptor de Antígeno de Linfócitos T , Condicionamento Pré-Transplante/métodos , Resultado do TratamentoRESUMO
Apheresis can remove pathogens and mediators that contribute to pathogenic inflammatory responses in diseases not generally considered to be "Hematologic." Erythrocytapheresis can remove intracellular pathogens such as Babesiosis. Plasmapheresis can remove mediators of the inflammatory response in conditions such as sepsis, chronic autoimmune urticaria and malignant pertussis. Leukapheresis can remove potentially harmful leukocytes in Crohn's Disease and malignant pertussis. While apheresis can remove all of these substances, the clinical efficacy and pathophysiologic changes that occur during apheresis in these conditions are largely unknown. Hence, the clinical utility of apheresis in these conditions is largely unknown and research in these areas has the potential to benefit many patients with a variety of diseases.
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Remoção de Componentes Sanguíneos , Infecções/terapia , Inflamação/terapia , Babesiose/sangue , Babesiose/parasitologia , Babesiose/terapia , Toxinas Bacterianas/sangue , Doença Crônica , Doença de Crohn/sangue , Doença de Crohn/terapia , Citocinas/sangue , Eritrócitos/parasitologia , Medicina Baseada em Evidências , Humanos , Infecções/sangue , Inflamação/sangue , Mediadores da Inflamação/sangue , Sepse/sangue , Sepse/terapia , Urticária/sangue , Urticária/terapia , Coqueluche/sangue , Coqueluche/terapiaRESUMO
BACKGROUND: Lenalidomide is an immunomodulatory drug with effects on the immune system that may enhance antibody-dependent cell-mediated cytotoxicity and reverse tumor-induced immune suppression. Furthermore, single-agent lenalidomide has therapeutic activity in relapsed/refractory B-cell lymphomas. These immunologic effects potentially may enhance the action of rituximab. METHODS: To test the efficacy of lenalidomide combined with rituximab, the authors conducted a phase 2 trial of lenalidomide, low-dose dexamethasone, and rituximab in patients who had rituximab-resistant, relapsed/refractory, indolent B-cell or mantle cell lymphomas. Patients received two 28-day treatment cycles of lenalidomide 10 mg daily and dexamethasone 8 mg once weekly (part I). During cycle 3, 4 weekly doses of rituximab 375 mg/m2 were administered with lenalidomide-dexamethasone (part II). After the part II response assessment, stable or responding patients continued to receive lenalidomide-dexamethasone. RESULTS: Twenty-seven patients with follicular (n=18), mantle cell (n=5), small lymphocytic (n=3), and marginal zone (n=1) lymphomas started therapy; 3 of 27 patients discontinued therapy because of adverse events and were not evaluable for response. For 24 patients, the overall response rate after part I was 29% (4 patients had a complete response [CR] or CR unconfirmed, and 3 patients had a partial response), and the overall response rate after part II was 58% (8 patients had a CR, and 6 patients had a partial response). For 27 patients, at a median follow-up of 12.2 months, the median progression-free survival was 23.7 months. CONCLUSIONS: The combination of lenalidomide, low-dose dexamethasone, and rituximab achieved high response rates with durable responses in patients with rituximab-resistant, indolent B-cell and mantle cell lymphomas. Overall response rate increased from 29% after two 28-day cycles of lenalidomide and low-dose dexamethasone to 58% after the addition of rituximab, suggesting that lenalidomide can overcome resistance to rituximab.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lenalidomida , Linfoma de Células B/mortalidade , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Rituximab , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Resultado do TratamentoRESUMO
Severe immune deficiency follows autologous stem cell transplantation for multiple myeloma and is associated with significant infectious morbidity. This study was designed to evaluate the utility of a pretransplantation vaccine and infusion of a primed autologous T-cell product in stimulating specific immunity to influenza. Twenty-one patients with multiple myeloma were enrolled from 2007 to 2009. Patients were randomly assigned to receive an influenza-primed autologous T-cell product or a nonspecifically primed autologous T-cell product. The study endpoint was the development of hemagglutination inhibition titers to the strain-specific serotypes in the influenza vaccine. Enzyme-linked immunospot assays were performed to confirm the development of influenza-specific B-cell and T-cell immunity. Patients who received the influenza-primed autologous T-cell product were significantly more likely to seroconvert in response to the influenza vaccine (P = .001). Seroconversion was accompanied by a significant B-cell response. No differences were observed in the global quantitative recovery of T-cell and B-cell subsets or in global T-cell and B-cell function. The provision of a primed autologous T-cell product significantly improved subsequent influenza vaccine responses. This trial was registered at www.clinicaltrials.gov as #NCT00499577.
Assuntos
Vacinas contra Influenza/uso terapêutico , Influenza Humana/imunologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Transplante de Células-Tronco , Linfócitos T/transplante , Transferência Adotiva , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Humanos , Vacinas contra Influenza/imunologia , Masculino , Pessoa de Meia-Idade , Transplante Autólogo , VacinaçãoRESUMO
In a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.
Assuntos
Imunoterapia/métodos , Mieloma Múltiplo/terapia , Fragmentos de Peptídeos/imunologia , Vacinação/métodos , Adulto , Idoso , Sequência de Aminoácidos , Antígenos de Neoplasias/imunologia , Terapia Combinada , Exantema/etiologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunoterapia/efeitos adversos , Imunoterapia Adotiva , Proteínas Inibidoras de Apoptose , Estimativa de Kaplan-Meier , Masculino , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/imunologia , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Náusea/etiologia , Survivina , Linfócitos T/imunologia , Linfócitos T/transplante , Telomerase/química , Telomerase/imunologia , Transplante Autólogo , Resultado do Tratamento , Vacinação/efeitos adversos , Vômito/etiologiaRESUMO
The costimulatory requirements required for peripheral blood T regulatory cells (Tregs) are unclear. Using cell-based artificial APCs we found that CD28 but not ICOS, OX40, 4-1BB, CD27, or CD40 ligand costimulation maintained high levels of Foxp3 expression and in vitro suppressive function. Only CD28 costimulation in the presence of rapamycin consistently generated Tregs that consistently suppressed xenogeneic graft-vs-host disease in immunodeficient mice. Restimulation of Tregs after 8-12 days of culture with CD28 costimulation in the presence of rapamycin resulted in >1000-fold expansion of Tregs in <3 wk. Next, we determined whether other costimulatory pathways could augment the replicative potential of CD28-costimulated Tregs. We observed that while OX40 costimulation augmented the proliferative capacity of CD28-costimulated Tregs, Foxp3 expression and suppressive function were diminished. These studies indicate that the costimulatory requirements for expanding Tregs differ from those for T effector cells and, furthermore, they extend findings from mouse Tregs to demonstrate that human postthymic Tregs require CD28 costimulation to expand and maintain potent suppressive function in vivo.
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Antígenos CD28/metabolismo , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Antígenos CD28/fisiologia , Técnicas de Cultura de Células , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Células K562 , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transdução de Sinais/imunologia , Linfócitos T Reguladores/transplante , Timo/citologia , Timo/imunologia , Timo/metabolismoRESUMO
Many recent advances in basic cell biology and immunology are a harbinger of progress in adoptive cell therapy (ACT) including (1) the finding that host lymphodepletion enhances engraftment and efficacy, (2) the recognition that in vitro T cell functions may not correlate with in vivo efficacy, and (3) the development of advanced ex vivo culture methods to expand lymphocytes to therapeutically effective numbers. In this article, we focus on the development of artificial antigen presenting cells (aAPCs) in our laboratory and their applicability to augment ACT protocols. We also describe how aAPCs can be used to broaden ACT to treat patients with a wide variety of cancers, chronic infectious diseases, and autoimmune manifestations.
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Células Apresentadoras de Antígenos/imunologia , Imunoterapia Adotiva/métodos , Linfócitos T/transplante , Animais , Humanos , Células K562 , Ativação Linfocitária/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/transplante , Linfócitos T/citologia , Linfócitos T/imunologiaRESUMO
Immune reconstitution following haematopoietic stem cell transplantation (SCT) is an often slow and incomplete process that leads to increased risk of infection and malignant disease. Immunization in SCT is frequently unsuccessful due to the prolonged lymphopenia, especially of CD4 T cells, seen following transplant. The transfusion of T cells, also called 'adoptive T-cell therapy', has the potential to enhance anti-tumour and overall immunity, and augment vaccine efficacy in the post-transplant setting. Recent advances in tissue culture, cellular immunology and tumour biology are guiding new approaches to adoptive T-cell therapy. This chapter will discuss the challenges that face the field before adoptive T-cell therapy can be translated into routine clinical practice.
Assuntos
Células-Tronco Hematopoéticas/imunologia , Imunoterapia Adotiva , Linfócitos T/imunologia , Linfócitos T/transplante , Transferência Adotiva/métodos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Humanos , Síndromes de Imunodeficiência/etiologia , Imunoterapia Adotiva/efeitos adversos , Depleção Linfocítica , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/métodos , Transplante HomólogoRESUMO
PURPOSE: Lenalidomide, an immunomodulatory agent that enhances antibody-dependent cell-mediated cytotoxicity, has the potential to synergize with rituximab, an anti-CD20 mAb. We hypothesized that the addition of lenalidomide to rituximab would improve clinical outcomes in patients with B-cell lymphomas who were previously rituximab resistant, defined as no response to or progression of lymphoma within 6 months of rituximab-based therapy. EXPERIMENTAL DESIGN: We conducted a single-center, phase II trial in patients with indolent B-cell or mantle cell lymphomas who were previously rituximab resistant. Patients received 10 mg lenalidomide daily for 8 weeks, and then received four weekly doses of 375 mg/m(2) rituximab; lenalidomide continued during and after rituximab. Response to therapy was assessed after 8 weeks of lenalidomide and 12 weeks after first dose of rituximab. The primary endpoint was overall response rate (ORR) after lenalidomide and rituximab. RESULTS: Fifty patients were enrolled and 43 patients completed both response assessments. ORR after 8 weeks of lenalidomide was 30.2%; 12 weeks after the addition of rituximab to lenalidomide, ORR increased to 62.8% (N = 43). For all patients (N = 50), median progression-free survival (PFS) is 22.2 months (median follow-up, 39.2 months). PFS after lenalidomide-rituximab was significantly longer than the PFS for the antecedent regimen used to define rituximab resistance (22.2 vs. 9.13 months, P = 0.0004). CONCLUSIONS: This trial is the first to show that the combination of lenalidomide and rituximab overcomes prior rituximab resistance in patients with indolent B-cell and mantle cell lymphomas.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Seguimentos , Genótipo , Humanos , Lenalidomida , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma de Células B/mortalidade , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Receptores de IgG/genética , Retratamento , Rituximab/administração & dosagem , Linfócitos T Reguladores/imunologia , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
PURPOSE: Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells. EXPERIMENTAL DESIGN: In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28-costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8(+) T cells, and ELISA performed serially after transplant. RESULTS: T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2(+) patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and 2-year event-free survival was 56% (95% CI, 37%-85%). CONCLUSIONS: A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine.
Assuntos
Antígenos de Neoplasias/imunologia , Carboximetilcelulose Sódica/análogos & derivados , Imunoterapia Adotiva , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Proteínas de Neoplasias/imunologia , Poli I-C/imunologia , Polilisina/análogos & derivados , Linfócitos T/imunologia , Adulto , Idoso , Vacinas Anticâncer/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunização , Imunoterapia Adotiva/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Polilisina/imunologia , Transplante Autólogo , Resultado do TratamentoRESUMO
Regulatory T cells (T(regs)) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25(+) FoxP3(+) T(regs) in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration-approved CD25-blocking monoclonal antibody daclizumab with regard to human T(reg) survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25(high) CD45RA(neg) T(regs). Moreover, daclizumab-treated CD45RA(neg) T(regs) lost suppressive function and regained the ability to produce interferon-γ, consistent with reprogramming. To understand the impact of daclizumab on T(regs) in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in T(regs) in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms T(regs) in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated T(regs) while avoiding autoimmunity.
Assuntos
Anticorpos Bloqueadores/uso terapêutico , Neoplasias da Mama/terapia , Reprogramação Celular/imunologia , Imunoterapia/métodos , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Depleção Linfocítica , Linfócitos T Reguladores/imunologia , Anticorpos Bloqueadores/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Terapia Combinada , Daclizumabe , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/imunologia , Antígenos Comuns de Leucócito/metabolismo , VacinaçãoRESUMO
To facilitate the therapeutic application of antigen-presenting cells (APCs), we have developed a cell-based artificial APC (aAPC) system by engineering K562 cells with lentiviruses to direct the stable expression and secretion of a variety of co-stimulatory molecules and cytokines. Here we report the use of a combinatorial lentiviral gene transfer approach to achieve long-term stable expression of at least seven genes in the K562 parental cell line. Expression of various combinations of genes on the aAPC enables the precise determination of human T-cell activation requirements, such that aAPCs can be tailored for the optimal propagation of T-cell subsets with specific growth requirements and distinct functions. The aAPCs support ex vivo growth and long-term expansion of functional human CD8 T cells without requiring the addition of exogenous cytokines, in contrast to the use of natural APCs. Distinct populations of T cells can be expanded with aAPCs expressing CD137L (4-1BBL) and/or CD80. Finally, the aAPCs provide an efficient platform to expand genetically modified T cells and to maintain CD28 expression on CD8 T cells. Therefore, K562-based aAPCs have therapeutic potential for adoptive immunotherapies and vaccinations.
Assuntos
Células Apresentadoras de Antígenos/metabolismo , Antígenos de Superfície/metabolismo , Citocinas/metabolismo , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Antígenos de Superfície/genética , Antígenos de Superfície/imunologia , Antígenos CD28/genética , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Humanos , Células K562 , Lentivirus/genética , Microscopia de Contraste de Fase , Receptores de IgG/genética , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Transdução Genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
T-cell post-transplant lymphoproliferative disorder (PTLD) is a rare life threatening complication of organ transplantation. It is usually resistant to treatment with reduction in immunosuppression or chemotherapy and carries a poor prognosis. We report on a combined kidney and pancreas transplant patient with Epstein-Barr virus (EBV) positive T-cell PTLD that had recurred after chemotherapy and reduction in immunosuppression. The patient was successfully treated with bexarotene, a novel synthetic retinoid analog, achieving a complete clinical response. Bexarotene may be a promising treatment for T-cell PTLD.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Transplante de Rim/efeitos adversos , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/etiologia , Anticarcinógenos/uso terapêutico , Bexaroteno , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4/isolamento & purificação , Humanos , Terapia de Imunossupressão , Linfoma de Células T Periférico/prevenção & controle , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Tetra-Hidronaftalenos/uso terapêutico , Carga ViralRESUMO
Post-transplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus (EBV) associated malignancy that occurs in the setting of pharmacologic immunosuppression used after organ transplantation. The presence of monoclonal gammopathy (MG) after organ transplantation is a risk factor for the development of PTLD. We retrospectively explored the characteristics of serum protein electrophoresis (SPEP) in 38 adult solid organ transplant patients with biopsy proven PTLD and SPEP. Twenty-three (61%) had MG with nine (24%) showing multiple MG. Background gammaglobulin levels were abnormal in 13 (34%) patients with five (13%) and eight (21%) having polyclonal hypergammaglobulinemia or hypogammaglobulinemia, respectively. Hypogammaglobulinemia was correlated with the presence of MG (p = 0.01) and polymorphic B-cell hyperplasia histology (p = 0.01). No correlation between SPEP findings and overall survival were noted. With median follow-up of 116 wk (range 2-261 wk), 21 (55%) patients are alive with 20 (53%) in complete remission. Response to reduction in immunosuppression was correlated with improved overall survival (262 wk vs. 68 wk, p = 0.003). Persistence of MG after complete response of the PTLD did not predict relapse. There is a high incidence of MG and gammaglobulin abnormalities in patients with PTLD.
Assuntos
Proteínas Sanguíneas/análise , Transtornos Linfoproliferativos/sangue , Transplante de Órgãos/efeitos adversos , Adulto , Idoso , Biomarcadores/sangue , Biópsia por Agulha , Eletroforese , Feminino , Citometria de Fluxo , Seguimentos , Rejeição de Enxerto/tratamento farmacológico , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of solid organ transplantation. Reduction in immunosuppression is usually the first line of therapy and is often curative. While undergoing treatment, imaging studies including MRI and CT scans are commonly used to follow the disease course. Laboratory studies such as lactate dehydrogenase and Epstein-Barr virus PCR can also be used to monitoring disease status. We report here a case of PTLD developing 48 months post renal transplant. A monoclonal protein (M protein) was demonstrated at diagnosis with a corresponding antibody expressed on the malignant lymphocytes. The patient was followed with serial serum protein electrophoreses (SPEP) to monitor his response to therapy. The amount of M protein paralleled the disease course, decreasing as the clinical symptoms improved. This case illustrates the utility of using SPEP to monitor patients with PTLD.
Assuntos
Proteínas Sanguíneas/química , Eletroforese/métodos , Transplante de Rim/efeitos adversos , Transtornos Linfoproliferativos/sangue , Adulto , Biópsia , Proteínas Sanguíneas/análise , Humanos , Imunoglobulina G/sangue , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Transtornos Linfoproliferativos/terapia , Masculino , Fatores de TempoRESUMO
Thrombotic thrombocytopenic purpura (TTP) was once uniformly fatal. Therapeutic plasma exchange in combination with immunosuppressive and anti-platelet agents, however, have resulted in improved survival rates of greater than 80% for patients with TTP. In spite of aggressive plasma exchange and adjuvant therapy, a number of TTP patients are refractory to treatment. In addition, up to 40% of TTP patients who initially respond to therapy eventually relapse. Alternative therapies such as splenectomy have been used with varying degrees of success in refractory and relapsing TTP patients. The usefulness of splenectomy in preventing relapse of TTP or treating those patients who are refractory to plasma exchange remains controversial. We present a single institution's experience with 14 patients who underwent splenectomy for refractory (six patients) or relapsed (eight patients) TTP since 1984. In both patient groups, splenectomy induced stable long-term remissions. Six of six (100%) patients who were refractory to plasma exchange, survived to be discharged from the hospital, apparently free of disease. Four of eight patients (50%) who had a splenectomy for relapsing TTP went into a complete remission and had no further relapses of their disease. Moreover, in relapsing patients who failed to experience long-term remission, the relapse rate after splenectomy was 0.3 events per patient year compared to 1.0 events per patient year prior to splenectomy. We conclude that splenectomy is a reasonable treatment option for TTP patients refractory to standard plasma exchange therapy or who have experienced multiple and/or complicated relapses. We believe this is the first series that demonstrates efficacy of splenectomy in plasma exchange-refractory TTP.