RESUMO
BACKGROUND: Natural killer (NK) cells are one of the main effector populations of immunotherapy with monoclonal antibody and cytokines, used in combination with chemotherapy to treat children with high-risk neuroblastoma on this phase II trial. However, the impact of chemoimmunotherapy on NK cell kinetics, phenotype, and function is understudied. METHODS: We prospectively examined NK cell properties from 63 children with newly diagnosed neuroblastoma enrolled in a phase II trial (NCT01857934) and correlated our findings with tumor volume reduction after 2 courses of chemoimmunotherapy. NK cell studies were conducted longitudinally during chemoimmunotherapy and autologous hematopoietic cell transplantation (autoHCT) with optional haploidentical NK cell infusion and additional immunotherapy. RESULTS: Chemoimmunotherapy led to significant NK cytopenia, but complete NK cell recovery reliably occurred by day 21 of each therapy course as well as after autoHCT. Haploidentical NK cell infusion elevated the NK cell count transiently during autoHCT. NK cell cytotoxicity increased significantly during treatment compared with diagnosis. In addition, NK cells maintained their ability to respond to cytokine stimulation in culture longitudinally. Unsupervised cluster analysis of CD56bright NK cell count and tumor volume at diagnosis and after two courses of chemoimmunotherapy identified two patient groups with distinct primary tumor sizes and therapy responses. CONCLUSION: After profound NK cytopenia due to chemoimmunotherapy, endogenously reconstituted NK cells exhibit enhanced NK cytotoxicity compared with pretherapy measurements. Our data suggest a relationship between CD56bright expression and tumor size before and after two courses of chemoimmunotherapy; however, future studies are necessary to confirm this relationship and its predictive significance. TRIAL REGISTRATION NUMBER: NCT01857934.
Assuntos
Imunoterapia/métodos , Células Matadoras Naturais/metabolismo , Neuroblastoma/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Cinética , Masculino , Estudos ProspectivosRESUMO
Consolidation therapies for children with intermediate- or high-risk acute myeloid leukemia (AML) are urgently needed to achieve higher cure rates while limiting therapy-related toxicities. We determined if adoptive transfer of natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA)-mismatched donors may prolong event-free survival in children with intermediate-risk AML who were in first complete remission after chemotherapy. Patients received cyclophosphamide (Day - 7), fludarabine (Days - 6 through - 2), and subcutaneous interleukin-2 (Days - 1, 1, 3, 5, 7, and 9). Purified, unmanipulated NK cells were infused on Day 0, and NK cell chimerism and phenotyping from peripheral blood were performed on Days 7, 14, 21, and 28. As primary endpoint, the event-free survival was compared to a cohort of 55 patients who completed chemotherapy and were in first complete remission but did not receive NK cells. Donor NK cell kinetics were determined as secondary endpoints. Twenty-one patients (median age at diagnosis, 6.0 years [range, 0.1-15.3 years]) received a median of 12.5 × 106 NK cells/kg (range, 3.6-62.2 × 106 cells/kg) without major side effects. All but 3 demonstrated transient engraftment with donor NK cells (median peak donor chimerism, 4% [range, 0-43%]). KIR-HLA-mismatched NK cells expanded in 17 patients (81%) and contracted in 4 (19%). However, adoptive transfer of NK cells did not decrease the cumulative incidence of relapse (0.393 [95% confidence interval: 0.182-0.599] vs. 0.35 [0.209-0.495]; P = .556) and did not improve event-free (60.7 ± 10.9% vs. 69.1 ± 6.8%; P = .553) or overall survival (84.2 ± 8.5% vs. 79.1 ± 6.6%; P = .663) over chemotherapy alone. The lack of benefit may result from insufficient numbers and limited persistence of alloreactive donor NK cells but does not preclude its potential usefulness during other phases of therapy, or in combination with other immunotherapeutic agents. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT00703820 . Registered 24 June 2008.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Células Matadoras Naturais/transplante , Leucemia Mieloide Aguda/terapia , Transplante Haploidêntico/métodos , Adolescente , Transferência Adotiva , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Quimioterapia de Consolidação , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Lactente , Interleucina-2/administração & dosagem , Interleucina-2/uso terapêutico , Masculino , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells.Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2-5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained.Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation.Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma. Clin Cancer Res; 23(21); 6441-9. ©2017 AACR.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Terapia Baseada em Transplante de Células e Tecidos , Gangliosídeos/antagonistas & inibidores , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Adolescente , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Etoposídeo/administração & dosagem , Feminino , Gangliosídeos/imunologia , Humanos , Ifosfamida/administração & dosagem , Lactente , Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/sangue , Irinotecano , Células Matadoras Naturais/imunologia , Masculino , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Neuroblastoma/sangue , Neuroblastoma/patologia , Temozolomida , Topotecan/administração & dosagem , Resultado do TratamentoRESUMO
We performed a retrospective analysis to evaluate clinical and economic outcomes in patients receiving remobilization therapy after primary mobilization failure. Our primary endpoint was to compare filgrastim plus plerixafor to other regimens in their ability to collect a target cell dose of at least 2 million CD34+ cells/kg (cumulative). Of 96 consecutive patients who failed their primary mobilization therapy and in whom a second mobilization was attempted, remobilization consisted of filgrastim plus plerixafor (n = 38), filgrastim with or without sargramostim (n = 43), or chemotherapy plus filgrastim (n = 15), 84% of filgrastim/plerixafor patients were able to collect at least 2 million CD34+ cells/kg from both mobilizations, compared to 60% of patients mobilized with chemotherapy/filgrastim and 79% of the filgrastim ± sargramostim patients (P = 0.17). However, when combined with cells collected from the first mobilization, 53% of filgrastim/plerixafor patients reached the target of 2 million CD34+ cells in one apheresis, compared to 20% of those receiving chemotherapy/filgrastim and 28% of those receiving filgrastim ± sargramostim (P = 0.02). Resource utilization, mobilization drug costs, clinical care costs, and total costs were significantly different. We conclude that while filgrastim/plerixafor is the most efficient remobilization strategy, those clinical benefits may not translate into lower cost, especially when multiple days of plerixafor administration are required.
Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/economia , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Adulto , Idoso , Antígenos CD34/sangue , Benzilaminas , Institutos de Câncer , Ciclamos , Custos de Medicamentos , Resistência a Medicamentos , Quimioterapia Combinada/economia , Feminino , Filgrastim , Florida , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/economia , Custos de Cuidados de Saúde , Transplante de Células-Tronco Hematopoéticas/economia , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/economia , Humanos , Transtornos Linfoproliferativos/economia , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/economia , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Transplante Autólogo/economiaRESUMO
BACKGROUND: There is evidence suggesting that sirolimus, in combination with tacrolimus, is active in the prevention of graft-versus-host disease. Sirolimus-based immune suppression may suppress alloreactive T cells, while sparing the survival and function of regulatory T cells. DESIGN AND METHODS: We conducted a randomized trial to compare the impact of sirolimus/tacrolimus against that of methotrexate/tacrolimus on the prevention of graft-versus-host disease and regulatory T-cell reconstitution. RESULTS: Seventy-four patients were randomized 1:1 to sirolimus/tacrolimus or methotrexate/tacrolimus, stratified for type of donor (sibling or unrelated) and the patients' age. The rate of grade II-IV acute graft-versus-host disease at 100 days was 43% (95% CI: 27-59%) in the sirolimus/tacrolimus group and 89% (95% CI: 72-96%) in the methotrexate/tacrolimus group (P<0.001). The rate of moderate/severe chronic graft-versus-host disease was 24% (95% CI: 7-47%) in the sirolimus/tacrolimus group and 64% (95% CI: 41-79%) in the methotrexate/tacrolimus group (P=0.008). Overall survival and patient-reported quality of life did not differ between the two groups. On days 30 and 90 post-transplant, sirolimus-treated patients had a significantly greater proportion of regulatory T cells among the CD4(+) cells in the peripheral blood, and isolated regulatory T cells were functional. CONCLUSIONS: These data demonstrate that sirolimus/tacrolimus prevents grade II-IV acute graft-versus-host disease and moderate-severe chronic graft-versus-host disease more effectively than does methotrexate/tacrolimus, and supports regulatory T-cell reconstitution following allogeneic hematopoietic cell transplantation.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia/diagnóstico , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico , Adulto , Idoso , Estudos de Casos e Controles , Terapia Combinada , Quimioterapia Combinada , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Estudos Prospectivos , Qualidade de Vida , Taxa de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Transplante Homólogo , Resultado do Tratamento , Adulto JovemAssuntos
Terapia Baseada em Transplante de Células e Tecidos , Neoplasias/etiologia , Complicações Pós-Operatórias , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/economia , Regulamentação Governamental , Humanos , Turismo Médico/legislação & jurisprudência , Turismo Médico/tendências , Neoplasias/prevenção & controle , Educação de Pacientes como Assunto , Direitos do Paciente , Guias de Prática Clínica como Assunto , Estados UnidosRESUMO
IMPORTANCE OF THE FIELD: Novel approaches are needed for patients with small cell lung cancer (SCLC), as response after relapse is poor with standard therapies. p53 gene mutations often occur, resulting in tumoral protein overexpression and allowing for their recognition by p53-specific cytotoxic T cells. AREAS COVERED IN THIS REVIEW: We describe the characteristics and manufacturing of INGN-225, a p53-modified adenovirus-tranduced dendritic cell vaccine, and review available data, to understand INGN-225's role in SCLC treatment. We discuss our pre-clinical, early Phase I/II, and ongoing randomized Phase II studies. WHAT THE READER WILL GAIN: INGN-225 was well tolerated (all toxicities Assuntos
Vacinas Anticâncer/uso terapêutico
, Células Dendríticas/imunologia
, Imunoterapia
, Neoplasias Pulmonares/imunologia
, Neoplasias Pulmonares/terapia
, Carcinoma de Pequenas Células do Pulmão/imunologia
, Carcinoma de Pequenas Células do Pulmão/terapia
, Proteína Supressora de Tumor p53/imunologia
, Animais
, Vacinas Anticâncer/administração & dosagem
, Vacinas Anticâncer/efeitos adversos
, Ensaios Clínicos Fase I como Assunto
, Ensaios Clínicos Fase II como Assunto
, Humanos
, Ensaios Clínicos Controlados Aleatórios como Assunto
RESUMO
BACKGROUND AIMS: Multiple cell-therapy products require density separation as a part of manufacturing. The traditional method for Ficoll separation, layering cell suspensions over Ficoll in tubes, followed by centrifugation and collection of cells from the interface, is too cumbersome and poses too high a risk of contamination for clinical-scale use. Recently, a system for clinical-scale Ficoll gradient applications has been introduced (Sepax) but this system has limited availability and is costly. METHODS: For preparations of mononuclear cells (MNC) for dendritic cell (DC) production, we developed a Ficoll separation protocol that employs the Haemonetics Cell Saver5 surgical blood salvage and wash instrument. This system uses standard blood bags and tubing, has single-use components, and is effectively closed. We analyzed 37 recent separation processes using this instrument and protocol. We measured depletion of red blood cells (RBC) and polymorphonuclear leukocytes (PMN), and recovery of CD14+ monocytes and MNC. RESULTS: Starting cell counts were 14.6 +/- 8.0 (x10(9)). Total cell recovery was 49.2 +/- 15.2%, RBC depletion was 88.4 +/- 2.8%, PMN depletion was 86.9 +/- 6.1%, MNC recovery was 63.6 +/- 5.0% and CD14+ monocyte recovery was 75.3 +/- 9.9%. CONCLUSIONS: The Cell Saver5 is relatively inexpensive to purchase and use. The instrument and its disposables are licensed by the United States Food and Drug Administration (FDA) for intra-operative blood salvage, and we have obtained approval for investigational use. Our method with this instrument has proven to be simple and efficient for clinical-scale Ficoll separations.
Assuntos
Separação Celular , Centrifugação com Gradiente de Concentração , Ficoll , Separação Celular/instrumentação , Separação Celular/métodos , Terapia Baseada em Transplante de Células e Tecidos , Centrifugação com Gradiente de Concentração/instrumentação , Centrifugação com Gradiente de Concentração/métodos , Células Dendríticas/citologia , Humanos , Leucócitos Mononucleares/citologia , Estados Unidos , United States Food and Drug AdministrationRESUMO
We have developed an approach for identifying primitive mobilized peripheral blood cells (PBSC) that express high levels of aldehyde dehydrogenase (ALDH). PBSC were stained with a fluorescent ALDH substrate, termed BODIPY trade mark -aminoacetaldehyde (BAAA), and then analysed using flow cytometry. A population of cells with a low side scatter (SSC) and a high level of BAAA staining, termed the SSCloALDHbr population, was readily discriminated and comprised a mean of 3 +/- 5% of leukapheresis samples. A mean of 73 +/- 11% of the SSCloALDHbr population expressed CD34 and 56 +/- 25% of all the mobilized CD34+ cells resided within the SSCloALDHbr population. The SSCloALDHbr population was largely depleted of cells with mature phenotypes and enriched for cells with immature phenotypes. Sorted SSCloALDHbr and SSCloALDHbr CD34+ PBSC were enriched for progenitors with the ability to (1) generate colony-forming units (CFU) and long-term culture (LTC)-derived CFU, (2) expand in primary and secondary LTC, and (3) generate multiple cell lineages. In 21 cancer patients who had undergone autologous PBSC transplantation, the number of infused SSCloALDHbr cells/kg highly correlated with the time to neutrophil and platelet engraftment (P < 0.015 and P < 0.003 respectively). In summary, peripheral blood SSCloALDHbr cells have the phenotypic and functional properties of primitive haematopoietic cells and their number correlates with engraftment following autologous transplantation.