RESUMEN
BACKGROUND: Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. METHODS: The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15-39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. DISCUSSION: CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. TRIAL REGISTRATION: Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).
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Cuidados Posteriores/métodos , Supervivientes de Cáncer/psicología , Adolescente , Adulto , Cuidados Posteriores/organización & administración , Niño , Depresión/psicología , Depresión/terapia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/complicaciones , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Ejercicio Físico/fisiología , Femenino , Humanos , Estilo de Vida , Masculino , Neoplasias/complicaciones , Neoplasias/psicología , Evaluación Nutricional , Medicina Preventiva/métodos , Medicina Preventiva/organización & administración , Factores de Riesgo , Encuestas y Cuestionarios , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: In 2014, we published the qPET method to quantify fluorodeoxyglucose positron emission tomography (FDG-PET) responses. Analysis of the distribution of the quantified signals suggested that a clearly abnormal FDG-PET response corresponds to a visual Deauville score (vDS) of 5 and high qPET values ≥ 2. Evaluation in long-term outcome data is still pending. Therefore, we analyzed progression-free survival (PFS) by early FDG-PET response in a subset of the GPOH-HD2002 trial for pediatric Hodgkin lymphoma (PHL). PATIENTS/METHODS: Pairwise FDG-PET scans for initial staging and early response assessment after two cycles of chemotherapy were available in 93 PHL patients. vDS and qPET measurement were performed and related to PFS. RESULTS: Patients with a qPET value ≥ 2.0 or vDS of 5 had 5-year PFS rates of 44%, respectively 50%. Those with qPET values < 2.0 or vDS 1 to 4 had 5-year PFS rates of 90%, respectively 80%. The positive predictive value of FDG-PET response assessment increased from 18% (9%; 33%) using a qPET threshold of 0.95 (vDS ≤ 3) to 30% (13%; 54%) for a qPET threshold of 1.3 (vDS ≤ 4) and to 56% (23%; 85%) when the qPET threshold was ≥ 2.0 (vDS 5). The negative predictive values remained stable at ≥92% (CI: 82%; 98%). CONCLUSION: Only strongly enhanced residual FDG uptake in early response PET (vDS 5 or qPET ≥ 2, respectively) seems to be markedly prognostic in PHL when treatment according to the GPOH-HD-2002 protocol is given.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorodesoxiglucosa F18/metabolismo , Enfermedad de Hodgkin/patología , Tomografía de Emisión de Positrones/métodos , Radiofármacos/metabolismo , Niño , Ensayos Clínicos como Asunto , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/metabolismo , Humanos , Masculino , Pronóstico , Curva ROC , Tasa de SupervivenciaRESUMEN
Engineering autologous or allogeneic T cells to express a suicide gene can control potential toxicity in adoptive T-cell therapies. We recently reported the development of a novel human suicide gene system that is based on an orphan human cytochrome P450 enzyme, CYP4B1, and the naturally occurring alkylator prodrug 4-ipomeanol. The goal of this study was to systematically develop a clinically applicable self-inactivating lentiviral vector for efficient co-expression of CYP4B1 as an ER-located protein with two distinct types of cell surface proteins, either MACS selection genes for donor lymphocyte infusions after allogeneic stem cell transplantation or chimeric antigen receptors for retargeting primary T cells. The U3 region of the myeloproliferative sarcoma virus in combination with the T2A site was found to drive high-level expression of our CYP4B1 mutant with truncated CD34 or CD271 as MACS suitable selection markers. This lentiviral vector backbone was also well suited for co-expression of CYP4B1 with a codon-optimized CD19 chimeric antigen receptor (CAR) construct. Finally, 4-ipomeanol efficiently induced apoptosis in primary T cells that co-express mutant CYP4B1 and the divergently located MACS selection and CAR genes. In conclusion, we here developed a clinically suited lentiviral vector that supports high-level co-expression of cell surface proteins with a potent novel human suicide gene.
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Hidrocarburo de Aril Hidroxilasas/genética , Genes Transgénicos Suicidas , Terapia Genética/métodos , Inmunoterapia Adoptiva/métodos , Antígenos CD34/genética , Antígenos CD34/metabolismo , Apoptosis , Hidrocarburo de Aril Hidroxilasas/metabolismo , Células Cultivadas , Vectores Genéticos/genética , Células HEK293 , Humanos , Células Jurkat , Lentivirus/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Terpenos/uso terapéuticoRESUMEN
Toxoplasmosis is a rare opportunistic infection in pediatric allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients and associated with severe T-cell deficiency. Here, we report the successful management of cerebral toxoplasmosis in a 15-year-old adolescent 4 months post allo-HSCT for non-Hodgkin lymphoma through rapid invasive diagnostics, long-term antiprotozoal chemotherapy, and an hematopoietic stem cell boost for persistently poor graft function. While supportive care and antiprotozoal chemotherapy achieved stabilization, definite improvement only occurred following recovery of CD4(+) T lymphocytes to >100 cells/µL. At 5 years after the diagnosis of toxoplasmosis, the patient is in continuing remission with normalized clinical and imaging findings.
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Antiprotozoarios/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfoma no Hodgkin/cirugía , Toxoplasma/efectos de los fármacos , Toxoplasmosis Cerebral/tratamiento farmacológico , Adolescente , Linfocitos T CD4-Positivos , Humanos , Huésped Inmunocomprometido , Infecciones Oportunistas/tratamiento farmacológico , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.
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Neoplasias Óseas/terapia , Conducta Cooperativa , Comunicación Interdisciplinaria , Sarcoma de Ewing/terapia , Neoplasias de los Tejidos Blandos/terapia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Óseas/mortalidad , Niño , Ensayos Clínicos como Asunto , Terapia Combinada , Progresión de la Enfermedad , Humanos , Terapia Neoadyuvante , Osteotomía , Radioterapia Adyuvante , Sarcoma de Ewing/mortalidad , Neoplasias de los Tejidos Blandos/mortalidad , Tasa de SupervivenciaRESUMEN
BACKGROUND: Novel treatment strategies in Ewing sarcoma include targeted cellular therapies. Preclinical in vivo models are needed that reflect their activity against systemic (micro)metastatic disease. METHODS: Whole-body magnetic resonance imaging (WB-MRI) was used to monitor the engraftment and dissemination of human Ewing sarcoma xenografts in mice. In this model, we evaluated the therapeutic efficacy of T cells redirected against the Ewing sarcoma-associated antigen GD2 by chimeric receptor engineering. RESULTS: Of 18 mice receiving intravenous injections of VH-64 Ewing sarcoma cells, all developed disseminated tumour growth detectable by WB-MRI. All mice had lung tumours, and the majority had additional manifestations in the bone, soft tissues, and/or kidney. Sequential scans revealed in vivo growth of tumours. Diffusion-weighted whole-body imaging with background signal suppression effectively visualised Ewing sarcoma growth in extrapulmonary sites. Animals receiving GD2-targeted T-cell therapy had lower numbers of pulmonary tumours than controls, and the median volume of soft tissue tumours at first detection was lower, with a tumour growth delay over time. CONCLUSION: Magnetic resonance imaging reliably visualises disseminated Ewing sarcoma growth in mice. GD2-retargeted T cells can noticeably delay tumour growth and reduce pulmonary Ewing sarcoma manifestations in this aggressive disease model.
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Neoplasias Óseas/terapia , Sarcoma de Ewing/terapia , Linfocitos T/inmunología , Animales , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Línea Celular Tumoral , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Gangliósidos/inmunología , Humanos , Inmunoterapia Adoptiva , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Sarcoma de Ewing/inmunología , Sarcoma de Ewing/patología , Imagen de Cuerpo Entero/métodos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.
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Neoplasias , Sistema de Registros , Adolescente , Austria/epidemiología , Niño , Preescolar , Ensayos Clínicos como Asunto/historia , Ensayos Clínicos como Asunto/métodos , Supervivencia sin Enfermedad , Femenino , Alemania/epidemiología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Lactante , Masculino , Estudios Multicéntricos como Asunto/historia , Estudios Multicéntricos como Asunto/métodos , Neoplasias/diagnóstico , Neoplasias/mortalidad , Neoplasias/terapia , Tasa de SupervivenciaRESUMEN
BACKGROUND: Novel treatment strategies are needed to cure disseminated Ewing sarcoma. Primitive neuroectodermal features and a mesenchymal stem cell origin are both compatible with aberrant expression of the ganglioside antigen G(D2) and led us to explore G(D2) immune targeting in this cancer. METHODS: We investigated G(D2) expression in Ewing sarcoma by immunofluorescence staining. We then assessed the antitumour activity of T cells expressing a chimeric antigen receptor specific for G(D2) against Ewing sarcoma in vitro and in vivo. RESULTS: Surface G(D2) was detected in 10 out of 10 Ewing sarcoma cell lines and 3 out of 3 primary cell cultures. Moreover, diagnostic biopsies from 12 of 14 patients had uniform G(D2) expression. T cells specifically modified to express the G(D2)-specific chimeric receptor 14. G2a-28ζ efficiently interacted with Ewing sarcoma cells, resulting in antigen-specific secretion of cytokines. Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, G(D2)-specific cytolytic responses to allogeneic and autologous Ewing sarcoma, including tumour cells grown as multicellular, anchorage-independent spheres. G(D2)-specific T cells further had activity against Ewing sarcoma xenografts. CONCLUSION: G(D2) surface expression is a characteristic of Ewing sarcomas and provides a suitable target antigen for immunotherapeutic strategies to eradicate micrometastatic cells and prevent relapse in high-risk disease.
Asunto(s)
Neoplasias Óseas/metabolismo , Gangliósidos/metabolismo , Sarcoma de Ewing/metabolismo , Linfocitos T/trasplante , Adolescente , Adulto , Animales , Antígenos de Superficie/inmunología , Antígenos de Superficie/metabolismo , Neoplasias Óseas/inmunología , Neoplasias Óseas/terapia , Línea Celular Tumoral , Proliferación Celular , Niño , Técnicas de Cocultivo , Citotoxicidad Inmunológica , Femenino , Gangliósidos/inmunología , Granzimas/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trasplante de Neoplasias , Receptores de Antígenos de Linfocitos T/biosíntesis , Receptores de Antígenos de Linfocitos T/metabolismo , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/metabolismo , Sarcoma de Ewing/inmunología , Sarcoma de Ewing/terapia , Anticuerpos de Cadena Única/biosíntesis , Anticuerpos de Cadena Única/metabolismo , Esferoides Celulares/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto JovenRESUMEN
Mutations of the hematopoietic transcription factor GATA1 (GATA1s) are pathognomonic in newborn with transient leukemia and children with Down syndrome and myeloid leukemia (ML-DS). Both TL and ML-DS can also occur in children with trisomy 21 mosaic.Between 2002 and 2011, 15 newborns and infants were diagnosed with DS mosaic. 9 of them presented with TL and 8 children suffered from ML-DS; 2 of them with a history of TL. In children without stigmata the special morphology and immunophenotype of blasts triggered the screening for GATA1 mutation and trisomy 21 mosaic.All newborns with TL achieved complete remission (CR). Due to clinical symptoms caused by the leukemic blasts, in 3 children low-dose cytarabine was applied. 1 patient died due to cardiac defect. In all patients GATA 1 s was confirmed. 6 children with ML-DS were initially treated according the AML-BFM protocol. After ML-DS was confirmed, therapy was continued with the intensity reduced schedule according to the ML-DS 2006 protocol. All children are still in CR (follow-up 1.8-7 years, median 2.7 yrs). 2 children with unknown trisomy 21 mosaic were diagnosed as acute megakaryoblastic leukemia (AMKL) and treated according the high risk arm of the AML-BFM 2004 including allogeneic stem cell transplantation in one child). GATA1 mutation was identified retrospectively. Both children are alive in CR.GATA1s associated leukemia has to be excluded in all young children with AMKL (<5 years old) to prevent overtreatment. Treatment with reduced intensity seems sufficient in children trisomy 21 mosaic and ML-DS.
Asunto(s)
Síndrome de Down/genética , Factor de Transcripción GATA1/genética , Leucemia Megacarioblástica Aguda/genética , Leucemia Mieloide Aguda/genética , Mosaicismo , Mutación , Mielopoyesis/genética , Trastornos Mieloproliferativos/genética , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Terapia Combinada , Citarabina/uso terapéutico , Síndrome de Down/diagnóstico , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Recién Nacido , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/tratamiento farmacológicoRESUMEN
Invasive aspergillosis (IA) at the insertion site of central venous catheters is a rare event. Here we report the occurrence of chest wall aspergillosis at the insertion site of a Broviac catheter in a 5-year-old child undergoing allogeneic hematopoietic stem cell transplantation. The infection arose during profound granulocytopenia under conditions of reverse isolation with laminar air flow and high efficiency particulate air filtration and was successfully managed with repeat surgical debridement, voriconazole/caspofungin combination therapy guided by therapeutic drug monitoring, and adjunctive use of granulocyte colony-stimulating factor. The case reflects the occurrence of IA despite reverse isolation and air decontamination, the principles of treatment of Aspergillus soft tissue infections in granulocytopenic patients, and the need for therapeutic drug monitoring of voriconazole particularly in young children.
Asunto(s)
Aspergilosis/etiología , Catéteres/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Pared Torácica/microbiología , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Caspofungina , Preescolar , Equinocandinas/uso terapéutico , Humanos , Lipopéptidos , Masculino , Pirimidinas/uso terapéutico , Trasplante Homólogo , Triazoles/uso terapéutico , VoriconazolRESUMEN
BACKGROUND: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). PATIENTS AND METHODS: The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. RESULTS: In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan-Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. CONCLUSIONS: The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755).
Asunto(s)
Antineoplásicos , Neoplasias Óseas , Osteosarcoma , Adolescente , Antineoplásicos/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Niño , Humanos , Radioisótopos de Yodo/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Compuestos de Fenilurea , Quinolinas , Adulto JovenRESUMEN
T cells can be engineered to target tumor cells by transduction of tumor-specific chimeric receptors, consisting of an extracellular antigen-binding domain and an intracellular signaling domain. However, the peripheral blood of cancer patients frequently contains an increased number of T regulatory cells, which appear to inhibit immune reactivity. We have investigated the effects of T regulatory cells on chimeric T cells specific for the B-cell antigen CD19, as B-cell malignancies are attractive targets for chimeric T-cell therapy. When a CD19 single-chain Fv antibody was coupled to the CD3 zeta (zeta) chain, there was sharply reduced activity on exposure to T regulatory cells, measured by CD19+ target-induced proliferation and cytotoxicity. By contrast, expression in T cells of a chimeric receptor consisting of the intracellular portion of the CD28 molecule fused to the zeta-chain and CD19 single-chain Fv not only produced a higher proliferative response and an increased nuclear factor kappaB activation but also sustained these activities in the presence of T regulatory cells. These effects are seen whether the chimeric T cells are derived from normal donors or from patients with B-cell chronic lymphocytic leukemia, indicating the potential for clinical application in B cell malignancies.
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Antígenos CD28/genética , Inmunoterapia Adoptiva/métodos , Leucemia Linfocítica Crónica de Células B/terapia , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T Citotóxicos/fisiología , Linfocitos T Reguladores/fisiología , Antígenos CD19/genética , Antígenos CD28/química , Complejo CD3/genética , División Celular/inmunología , Citocinas/metabolismo , Citometría de Flujo , Humanos , Células K562 , Leucemia Linfocítica Crónica de Células B/inmunología , Proteínas Mutantes Quiméricas/química , Proteínas Mutantes Quiméricas/genética , FN-kappa B/metabolismo , Estructura Terciaria de Proteína , Receptores de Antígenos de Linfocitos T/química , Transducción de Señal/fisiología , Linfocitos T Citotóxicos/citología , Linfocitos T Reguladores/citología , Transducción GenéticaRESUMEN
Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein-Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10-4) post first stem cell transplant (SCT), or prophylactically post second SCT. An initial cohort showed poor expansion/persistence. We therefore investigated EBV-directed vaccination to enhance expansion/persistence. Eleven patients were treated. No CRS, neurotoxicity or graft versus host disease (GVHD) was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de novo), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Although CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range: 0-28) days without vaccination compared to 56 (range: 0-221) days with vaccination (P=0.06). This study demonstrates the feasibility of multi-center studies of CAR T cell therapy and the potential for enhancing persistence with vaccination.
Asunto(s)
Antígenos CD19 , Inmunoterapia Adoptiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T Citotóxicos/trasplante , Niño , Preescolar , Quimera , Femenino , Herpesvirus Humano 4 , Humanos , Inmunoterapia/métodos , Masculino , Receptores de Antígenos de Linfocitos T/inmunología , Recurrencia , Linfocitos T Citotóxicos/virología , VacunaciónRESUMEN
Background. Preclinical data indicate that trabectedin followed by irinotecan has strong synergistic effects on Ewing sarcoma. This is presumably due to hypersensitization of the tumor cells to the camptothecin as an effect of trabectedin in addition to synergistic suppression of EWS-FLI1 downstream targets. A strong effect was also reported in a human rhabdomyosarcoma xenograft. Procedure. Twelve patients with end-stage refractory translocation-positive sarcomas were treated with trabectedin followed by irinotecan within a compassionate use program. Eight patients had Ewing sarcoma and four patients had other translocation-positive sarcomas. Results. Three-month survival rate was 0.75 after the start of this therapy. One patient achieved a partial response according to RECIST criteria, five had stable disease, and the remaining six progressed through therapy. The majority of patients experienced significant hematological toxicity (grades 3 and 4). Reversible liver toxicity and diarrhea also occurred. Conclusions. Our experience with the combination of trabectedin followed with irinotecan in patients with advanced sarcomas showed promising results in controlling refractory solid tumors. While the hematological toxicity was significant, it was reversible. Quality of life during therapy was maintained. These observations encourage a larger clinical trial.
RESUMEN
The rate of ara-cytosine triphosphate (ara-CTP) accumulation and its retention has been correlated with 1-beta-D-arabinofuranosylcytosine (ara-C)-mediated toxicity and clinical outcome in childhood and adult leukemia. We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine (F-ara-A) and hydroxyurea (HU) enhanced ara-CTP levels in two human myeloid (HL-60, CMK) and two lymphoblastic leukemia cell lines (MOLT-4, BLIN-1) and also in blasts from 28 children with acute leukemia (AML: 14, ALL: 14). Incubation experiments carried out with cell lines showed F-ara-A and HU to be equipotent in increasing ara-CTP levels. The highest increase was observed in HL-60 cells whereas preincubation had no modulatory effect in MOLT-4 cells. Accordingly, modulation of intracellular ara-CTP levels differed between the subtypes of childhood acute leukemia: whereas in T-ALL (five) preincubation with F-ara-A and HU had no effect on intracellular ara-C metabolism, increased ara-CTP levels were seen in some cases of pre-B-ALL (seven). In myelogenous blasts (12) clinically relevant enhancement of ara-C toxification was regularly obtained with both, F-ara-A (1.9-fold) and HU (1.5-fold). In conclusion, our data suggest that combinations of ara-C and ribonucleotide reductase inhibitors are apt to increase ara-CTP levels depending on the individual cell type and its sensitivity towards ara-C modulators.
Asunto(s)
Antineoplásicos/farmacología , Trifosfato de Arabinofuranosil Citosina/metabolismo , Hidroxiurea/farmacología , Leucemia/metabolismo , Vidarabina/análogos & derivados , Vidarabina/farmacología , Adulto , Células HL-60 , HumanosRESUMEN
Although BCR-ABL+ stem cells in chronic myeloid leukemia (CML) resist elimination by targeted pharmacotherapy in most patients, immunological graft-versus-leukemia effects can cure the disease. Besides cytotoxic T cells, natural killer (NK) cells may have a role in immune control of CML. Here, we explored the functionality of NK cells in CML patients and in a transgenic inducible BCR-ABL mouse model. Compared with controls, NK-cell proportions among lymphocytes were decreased at diagnosis of CML and did not recover during imatinib-induced remission for 10-34 months. Functional experiments revealed limited in vitro expansion of NK cells from CML patients and a reduced degranulation response to K562 target cells both at diagnosis and during imatinib therapy. Consistent with the results in human CML, relative numbers of NK1.1+ NK cells were reduced following induction of BCR-ABL expression in mice, and the defects persisted after BCR-ABL reversion. Moreover, target-induced degranulation by expanded BCR-ABL+ NK cells was compromised. We conclude that CML is associated with quantitative and functional defects within the NK-cell compartment, which is reproduced by induced BCR-ABL expression in mice. Further work will aim at identifying the mechanisms of NK-cell deficiency in CML and at developing strategies to exploit NK cells for immunotherapy.