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1.
Nat Rev Drug Discov ; 19(3): 185-199, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900462

RESUMO

Autologous chimeric antigen receptor (CAR) T cells have changed the therapeutic landscape in haematological malignancies. Nevertheless, the use of allogeneic CAR T cells from donors has many potential advantages over autologous approaches, such as the immediate availability of cryopreserved batches for patient treatment, possible standardization of the CAR-T cell product, time for multiple cell modifications, redosing or combination of CAR T cells directed against different targets, and decreased cost using an industrialized process. However, allogeneic CAR T cells may cause life-threatening graft-versus-host disease and may be rapidly eliminated by the host immune system. The development of next-generation allogeneic CAR T cells to address these issues is an active area of research. In this Review, we analyse the different sources of T cells for optimal allogeneic CAR-T cell therapy and describe the different technological approaches, mainly based on gene editing, to produce allogeneic CAR T cells with limited potential for graft-versus-host disease. These improved allogeneic CAR-T cell products will pave the way for further breakthroughs in the treatment of cancer.


Assuntos
Doença Enxerto-Hospedeiro/terapia , Imunoterapia/métodos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante , Doença Enxerto-Hospedeiro/imunologia , Humanos , Neoplasias/imunologia , Transplante Homólogo
2.
J Hematol Oncol ; 11(1): 81, 2018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29895316

RESUMO

The original article contains several small errors. The errors & concurrent corrections are listed below [1].

3.
Leukemia ; 32(2): 574, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29303505

RESUMO

This corrects the article DOI: 10.1038/leu.2017.290.

5.
Blood Cancer J ; 6(6): e430, 2016 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-27258611

RESUMO

Despite the impressive clinical efficacy of T cells engineered to express chimeric antigen receptors (CAR-Ts), the current applications of CAR-T cell therapy are limited by major treatment-related toxicity. Thus, safer yet effective alternative approaches must be developed. In this study, we compared CD19 bispecific T-cell engager (BiTE)-transferred T cells that had been transfected by RNA electroporation with CD19 CAR RNA-transferred T cells both in vitro and in an aggressive Nalm6 leukemia mouse model. BiTEs were secreted from the transferred T cells and enabled both the transferred and bystander T cells to specifically recognize CD19(+) cell lines, with increased tumor killing ability, prolonged functional persistence, increased cytokine production and potent proliferation compared with the CAR-T cells. More interestingly, in comparison with CD3/CD28 bead-stimulated T cells, T cells that were expanded by a rapid T-cell expansion protocol (REP) showed enhanced anti-tumor activities for both CAR and BiTE RNA-electroporated T cells both in vitro and in a Nalm6 mouse model (P<0.01). Furthermore, the REP T cells with BiTE RNAs showed greater efficacy in the Nalm6 leukemia model compared with REP T cells with CAR RNA (P<0.05) and resulted in complete leukemia remission.


Assuntos
Antígenos CD19/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Imunoterapia Adotiva , Leucemia/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19/genética , Linhagem Celular Tumoral , Humanos , Leucemia/patologia , Leucemia/terapia , Ativação Linfocitária/imunologia , Camundongos , Proteínas de Fusão Oncogênica/genética , Receptores de Antígenos/genética , Receptores de Antígenos/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/transplante , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Bone Marrow Transplant ; 51(9): 1204-10, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27159174

RESUMO

The optimal autologous stem cell rescue (HDC-SCR) regimen for children with high-risk neuroblastoma (HR-NBL) is not defined. Carboplatin/etoposide/melphalan (CEM) is the current US standard; however, European data suggest busulfan/melphalan (Bu/Mel) may have less toxicity. Published data regarding toxicities associated with CEM and Bu/Mel are limited. We conducted a single-institution retrospective cohort study of children with HR-NBL who received CEM or Bu/Mel preparative regimens. Toxicity data were analyzed using χ(2) or Fisher's exact, Wilcoxon two-sample or log-rank tests. Sinusoidal obstruction syndrome (SOS) was observed in 7/44 CEM (15.9%) and 5/21 (24%) Bu/Mel patients (P=0.50). Median time to SOS was longer following Bu/Mel than CEM (20 versus 9 days, P=0.02). Pulmonary hypertension (PHTN) was observed in ~20% of children after Bu/Mel and none after CEM (P=0.01). CEM patients had more nephrotoxicity (P=0.001), packed red blood cell (P=0.02) and platelet transfusions (P=0.008), and days on maximum pain support (P=0.0007). Time to engraftment, length of stay, documented infection rates and HDC-SCR-related mortality were similar. Nephrotoxicity and resource utilization associated with cytopenias and mucositis were greater after CEM. Pulmonary toxicities were more severe after Bu/Mel, and increased vigilance for PHTN may be warranted, particularly in children with hypoxemia out of proportion to respiratory distress.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Agonistas Mieloablativos/toxicidade , Neuroblastoma/complicações , Neuroblastoma/tratamento farmacológico , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/administração & dosagem , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Estudos de Coortes , Etoposídeo/administração & dosagem , Feminino , Hepatopatia Veno-Oclusiva/induzido quimicamente , Humanos , Hipertensão Pulmonar/induzido quimicamente , Lactente , Nefropatias/induzido quimicamente , Masculino , Melfalan/administração & dosagem , Mucosite/induzido quimicamente , Agonistas Mieloablativos/administração & dosagem , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Pancitopenia/induzido quimicamente , Estudos Retrospectivos , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/métodos , Transplante de Células-Tronco/mortalidade , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Adulto Jovem
8.
Bone Marrow Transplant ; 50(9): 1173-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25961775

RESUMO

We previously showed that minimal residual disease (MRD) detection pre-hematopoietic cell transplant (HCT) and acute GvHD (aGvHD) independently predicted risk of relapse in pediatric ALL. In this study we further define risk by assessing timing of relapse and the effects of leukemia risk category and post-HCT MRD. By multivariate analysis, pre-HCT MRD <0.1% and aGvHD by day +55 were associated with decreased relapse and improved event-free survival (EFS). Intermediate leukemia risk status predicted decreased relapse, and improved EFS and overall survival (OS). Patients with pre-HCT MRD ⩾0.1% who did not develop aGvHD compared with those with MRD <0.1% who did develop aGvHD had much worse survival (2 years EFS 18% vs 71%; P=0.001, 2 years OS 46 vs 74%; P=0.04). Patients with pre-HCT MRD <0.1% who did not experience aGvHD had higher rates of relapse than those who did develop aGvHD (40% vs 13%; P= 0.008). Post-HCT MRD led to a substantial increase in relapse risk (HR=4.5, P<0.01). Patients at high risk of relapse can be defined after transplant using leukemia risk category, presence of MRD pre or post HCT, and occurrence of aGvHD. An optimal window to initiate intervention to prevent relapse occurs between day +55 and +200 after HCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/prevenção & controle , Recidiva , Taxa de Sobrevida , Fatores de Tempo
9.
Bone Marrow Transplant ; 48(8): 1056-64, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23419433

RESUMO

Although the role of autologous hematopoietic cell transplantation (auto-HCT) is well established in neuroblastoma (NBL), the role of allogeneic HCT (allo-HCT) is controversial. The Center for International Blood and Marrow Transplant Research conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto-HCT (n=46 and 97, respectively). One-year and five-year OS were 59% and 29% for Group 1 and 50% and 7% for Group 2, respectively. Among donor types, disease-free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not at 5 years post HCT. Patients in CR or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared with those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared with those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Neuroblastoma/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Coleta de Dados , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Autólogo , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
10.
Bone Marrow Transplant ; 48(7): 947-52, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23334272

RESUMO

Increasing treatment intensity has improved outcomes for children with neuroblastoma. We performed a pilot study in the Children's Oncology Group to assess the feasibility and toxicity of a tandem myeloablative regimen without TBI supported by autologous CD34-selected peripheral blood stem cells. Forty-one patients with high-risk neuroblastoma were enrolled; eight patients did not receive any myeloablative consolidation procedure and seven received only one. Two patients out of 41 (4.9%) experienced transplant-related mortality. CD34 selection was discontinued after subjects were enrolled due to serious viral illness. From the time of study enrollment, the overall 3-year EFS and OS were 44.8 ± 9.6% and 59.2 ± 9.2% (N=41). These results demonstrate that tandem transplantation in the cooperative group setting is feasible and support a randomized comparison of single vs tandem myeloablative consolidation with PBSC support for high-risk neuroblastoma.


Assuntos
Neuroblastoma/mortalidade , Neuroblastoma/terapia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante/métodos , Autoenxertos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Projetos Piloto , Condicionamento Pré-Transplante/efeitos adversos , Viroses/etiologia , Viroses/mortalidade
11.
Bone Marrow Transplant ; 47(11): 1409-14, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22504933

RESUMO

Mucositis can be a serious complication of hematopoietic SCT (HSCT). A previous phase II trial in 32 children undergoing HSCT reported a beneficial effect of the homeopathic remedy Traumeel S. The Children's Oncology Group sought to replicate the results in a multi-institutional trial. The study was an international multi-center, double-blind, randomized trial comparing Traumeel with placebo in patients aged 3-25 years undergoing myeloablative HSCT. Traumeel/placebo was started on Day -1 as a five-time daily mouth rinse. Efficacy of the treatment was assessed using the modified Walsh scale for mucositis, scored daily from Day -1 to 20 days after HCST. The main outcome was the sum of Walsh scale scores (area-under-the-curve (AUC)) over this period. Other outcomes included narcotic use, days of total parenteral feeding, days of nasogastric feeding and adverse events. In 181 evaluable patients, there was no statistical difference in mucositis (AUC) in the Traumeel group (76.7) compared with placebo (67.3) (P=0.13). There was a trend towards less narcotic usage in the Traumeel patients. No statistically beneficial effect from Traumeel was demonstrated for mucositis. We could not confirm that Traumeel is an effective treatment for mucositis in children undergoing HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Minerais/uso terapêutico , Mucosite/etiologia , Mucosite/terapia , Extratos Vegetais/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Homeopatia/métodos , Humanos , Masculino , Mucosite/tratamento farmacológico , Mucosite/prevenção & controle , Resultado do Tratamento , Adulto Jovem
12.
Leukemia ; 26(2): 271-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21844871

RESUMO

Although the cure rate of newly diagnosed acute lymphoblastic leukemia (ALL) has improved over the past four decades, the outcome for patients who relapse remains poor. New therapies are needed for these patients. Our previous global gene expression analysis in a series of paired diagnosis-relapse pediatric patient samples revealed that the antiapoptotic gene survivin was consistently upregulated upon disease relapse. In this study, we demonstrate a link between survivin expression and drug resistance and test the efficacy of a novel antisense agent in promoting apoptosis when combined with chemotherapy. Gene-silencing experiments targeting survivin mRNA using either short-hairpin RNA (shRNA) or a locked antisense oligonucleotide (LNA-ON) specifically reduced gene expression and induced apoptosis in leukemia cell lines. When used in combination with chemotherapy, the survivin shRNA and LNA-ON potentiated the chemotherapeutic antileukemia effect. Moreover, in a mouse primary xenograft model of relapse ALL, the survivin LNA-ON decreased survivin expression in a subset of animals, and produced a statistically significant decrease in tumor progression. Taken together, these findings suggest that targeting endogenous levels of survivin mRNA by LNA-ON methods may augment the response to standard chemotherapy by sensitizing otherwise resistant tumor cells to chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Técnicas de Silenciamento de Genes , Proteínas Inibidoras de Apoptose/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Sequência de Bases , Primers do DNA , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Survivina , Resultado do Tratamento
14.
Bone Marrow Transplant ; 45(11): 1653-7, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20190833

RESUMO

Our group previously demonstrated a strong association between elevated plasma soluble CD13 enzyme activity and newly diagnosed extensive chronic GVHD (cGVHD) in children. As cytotoxic anti-CD13 Abs have been documented after blood and marrow transplant (BMT) in association with CMV infection and cGVHD, we hypothesized that soluble CD13 contributes to cGVHD pathogenesis by induction of CD13 reactive Abs and that anti-CD13 Abs could be additional biomarkers for newly diagnosed pediatric extensive cGVHD. Using prospectively collected plasma samples from pediatric allogeneic BMT (allo-BMT) subjects with cGVHD and controls without cGVHD enrolled in a large multi-institution Children's Oncology Group cGVHD therapeutic trial, we evaluated whether soluble CD13 correlates with induction of anti-CD13 Abs. We found that CD13 reactive Abs are present in a proportion of patients after allo-BMT, but did not seem to correlate with the presence of soluble CD13. Anti-CD13 Abs also did not meet our criteria as a diagnostic biomarker for cGVHD. These data do not confirm that induction of CD13 reactive Abs is a mechanism for cGVHD in children nor are part of the pathogenesis of cGVHD associated with elevated soluble CD13. The exact role of CD13 in cGVHD remains to be determined.


Assuntos
Anticorpos/imunologia , Transplante de Medula Óssea/imunologia , Antígenos CD13/imunologia , Doença Enxerto-Hospedeiro/imunologia , Adolescente , Anticorpos/sangue , Biomarcadores/sangue , Antígenos CD13/metabolismo , Criança , Pré-Escolar , Doença Crônica , Método Duplo-Cego , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Humanos , Hidroxicloroquina/uso terapêutico , Masculino
15.
Bone Marrow Transplant ; 41(2): 159-65, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18037943

RESUMO

High-risk neuroblastoma is a childhood malignancy with a poor prognosis. Gradual improvements in survival have correlated with therapeutic intensity, and the ability to harvest, process and store autologous hematopoietic stem cells has allowed for dose intensification beyond marrow tolerance. The use of high-dose chemotherapy with autologous hematopoietic stem cell rescue in consolidation has resulted in improvements in survival, although further advances are still needed. Newer approaches to SCT and supportive care, most notably the transition to PBSC, have resulted in further improvement in survival and decreases in treatment-related mortality. Research into experimental approaches to hematopoietic SCT is ongoing.


Assuntos
Tratamento Farmacológico/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Neuroblastoma/terapia , Transplante de Células-Tronco de Sangue Periférico , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos
16.
Bone Marrow Transplant ; 35(4): 361-7, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15608659

RESUMO

The use of peripheral blood stem cells (PBSC) for allogeneic transplants in adults has greatly increased. This trend is reflected in pediatrics, where healthy children increasingly are donating PBSC or donor lymphocyte infusion (DLI) via apheresis for use by ill siblings. There is a potential concern that the risks of PBSC collection may differ for pediatric donors. However, no large studies have assessed safety issues in this population. To address this need, we reviewed 218 (213 PBSC, five DLI) collections in 201 normal pediatric donors (8 months to 17 years, median 11.8 years) at 22 institutions in the Pediatric Blood and Marrow Transplant Consortium. Donors received a median of 4 days of growth factor, and mean collection yield was 9.1 x 10(6) CD34+ cells/kg recipient weight. Younger age, days of apheresis, and male gender predicted increased yield of CD34+ cells/kg donor weight. Growth factor-induced pain was mild and reported in less than 15% of patients. Most donors <20 kg (23/25, 92%) required PRBC priming of the apheresis machine. This experience with over 200 collections demonstrates that PBSC collection is safe in normal pediatric donors and desired CD34 cell yields are easily achieved. Younger children utilize more medical resources and children <20 kg usually require a single blood product exposure.


Assuntos
Doadores de Sangue , Mobilização de Células-Tronco Hematopoéticas/normas , Transplante de Células-Tronco Hematopoéticas/normas , Transfusão de Linfócitos/normas , Segurança/normas , Adolescente , Criança , Pré-Escolar , Mobilização de Células-Tronco Hematopoéticas/tendências , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Lactente , Leucaférese/normas , Leucaférese/tendências , Transfusão de Linfócitos/tendências , Masculino , Transplante Homólogo
17.
Bone Marrow Transplant ; 33(6): 651-7, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14730339

RESUMO

The risk of Epstein-Barr virus lymphoproliferative disease (EBV-LPD) increases with the use of highly immunosuppressive therapies. Allogeneic BMT, especially supported by T-cell-depleted stem cell products, is a risk factor for EBV-LPD. Although the risk of EBV-LPD after autologous transplantation is low, case reports of this complication in the autologous setting exist. We report a higher incidence than previously described of EBV-LPD in children undergoing sequential high-dose chemotherapy supported with CD34 selected peripheral blood stem cells (CD34+ PBSC). The median time to LPD after tandem transplant was 3 months (range 1-5 months). Five patients out of 156 (3.5%) developed EBV-LPD while enrolled on two trials of tandem autologous SCT in high-risk pediatric malignancies. Both studies employed five cycles of induction therapy, followed by tandem autologous PBSC transplants. In all, 108 out of 156 patients received CD34+ PBSC; 48 received unselected PBSC. All patients contracting LPD were from the CD34 selected group. Treatment of EBV-LPD included rituximab in four out of five patients, i.v.Ig in two out of five patients, and gancyclovir in two out of five patients. EBV-LPD resolved in four out of five patients. We conclude that the combination of tandem SCT and CD34 selection may have increased immunosuppression in these patients to a point where there is an elevated risk of EBV-LPD.


Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Transtornos Linfoproliferativos/virologia , Neuroblastoma/terapia , Transplante de Células-Tronco/métodos , Antígenos CD/sangue , Antígenos CD34/imunologia , Pré-Escolar , Feminino , Humanos , Incidência , Transtornos Linfoproliferativos/epidemiologia , Masculino , Transplante de Células-Tronco/efeitos adversos , Transplante Autólogo/efeitos adversos
18.
Clin Cancer Res ; 7(4): 977-84, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11309349

RESUMO

Tumor vascularity is highly correlated with disease outcome in neuroblastoma. Thus, novel therapeutics that target the vascular endothelium are candidates for incorporation into clinical trials. We therefore examined the effect of TNP-470 on human neuroblastoma growth in mouse models reflecting both clinically evident and minimal disease. Mice were inoculated s.c. or by tail vein injection with 10(7) human neuroblastoma-derived CHP-134 cells and treated with TNP-470 (100 mg/kg/dose s.c. three times a week or by continuous infusion) or saline. Treatment was given as a single agent in established xenografts, 10 days after 450 mg/kg of cyclophosphamide, or 12 h after tumor inoculation. Tumor growth rate was markedly inhibited in mice receiving TNP-470 administered alone both s.c. and by continuous infusion with a treatment to control ratio (T:C) at day 16 of 0.3 (P < 0.001) and a T:C at day 30 of 0.4 (P = 0.029) for each dosing method, respectively. TNP-470 also significantly inhibited tumor growth when administered following cyclophosphamide (T:C at day 30 = 0.2, P < 0.001) and inhibited disease establishment when given shortly after xenograft inoculation (T:C at day 30 = 0.1, P < 0.001) or tail vein injection. TNP-470 was shown to directly inhibit angiogenesis by Matrigel assay (P =.010) and to increase the apoptotic index in treated tumors. These data show that TNP-470 is a potent inhibitor of human neuroblastoma growth rate and tumorigenicity. We speculate that TNP-470 may be a useful adjuvant therapy for high-risk neuroblastoma patients, particularly when used in settings of minimal disease status.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neuroblastoma/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Animais , Apoptose , Divisão Celular/efeitos dos fármacos , Cicloexanos , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Neovascularização Patológica/prevenção & controle , Neovascularização Fisiológica/efeitos dos fármacos , O-(Cloroacetilcarbamoil)fumagilol , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Clin Cancer Res ; 7(4): 1026-32, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11309354

RESUMO

High-dose therapy with stem cell rescue is a treatment option for patients with advanced solid tumors. Although this approach has promise for some pediatric cancers, especially neuroblastoma, it is limited by the risk of relapse posttransplant as well as concern about possible reinfused tumor cells in autologous stem cell products. Antiangiogenic agents given during and after recovery from high-dose therapy with stem cell rescue may decrease the risk of relapse. TNP-470 is an antiangiogenic agent now in clinical trials. Although it inhibits the growth of bone marrow (BM) colony-forming cells in vitro, no significant hematological toxicity has been seen in Phase I trials. To assess the feasibility of using antiangiogenic agents during the period of posttransplant hematopoietic engraftment, we have developed a model of stem cell transplant in mice. Mice were lethally irradiated and then rescued with stem cells containing a transgene expressed in the hematopoietic lineage. Mice were then treated with TNP-470 or placebo, and assessed for survival, successful engraftment, and kinetics of engraftment. Both treated and control mice demonstrated reliable multilineage engraftment as well as normal lymphoid maturation with no excess mortality in the treated group. WBCs were lower but still within the normal range at d+28 in mice treated with bolus TNP-470, but not in those treated with continuous infusion TNP-470, compared with controls. These data indicate that inhibitors of angiogenesis do not adversely impact engraftment after stem cell transplantation.


Assuntos
Inibidores da Angiogênese/farmacologia , Transplante de Medula Óssea , Medula Óssea/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Ensaio de Unidades Formadoras de Colônias , Cicloexanos , Modelos Animais de Doenças , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Camundongos Transgênicos , Mortalidade , O-(Cloroacetilcarbamoil)fumagilol , Reprodutibilidade dos Testes
20.
Med Pediatr Oncol ; 35(6): 673-6, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11107144

RESUMO

UNLABELLED: Background and Procedure High-risk neuroblastoma disease features are correlated with tumor vascularity, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. We therefore examined the efficacy of TNP-470 (TAP Pharmaceuticals, Deerfield, IL) in human neuroblastoma xenograft models. RESULTS: Tumor growth rate was markedly inhibited in mice receiving TNP-470 administered alone with a treatment to control ratio (T/C) at day 21 = 0.4 (P <.001). TNP-470 also significantly inhibited tumorigenicity when administered shortly after xenograft inoculation (T/C at day 30 = 0.1, P <.001) and when administered following cyclophosphamide (T/C at day 35 = 0.1, P <.001). CONCLUSIONS: These data show that TNP-470 is a potent inhibitor of human neuroblastoma growth both alone and when given with conventional chemotherapy, suggesting that it may be a useful adjunctive therapy for high-risk neuroblastoma patients.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neuroblastoma/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Animais , Criança , Cicloexanos , Humanos , Camundongos , Camundongos Nus , Neoplasia Residual , O-(Cloroacetilcarbamoil)fumagilol , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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