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1.
Cell ; 186(19): 4216-4234.e33, 2023 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-37714135

RESUMEN

Chronic stimulation can cause T cell dysfunction and limit the efficacy of cellular immunotherapies. Improved methods are required to compare large numbers of synthetic knockin (KI) sequences to reprogram cell functions. Here, we developed modular pooled KI screening (ModPoKI), an adaptable platform for modular construction of DNA KI libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors (SRs). Over 30 ModPoKI screens across human TCR- and CAR-T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct that enhanced fitness of chronically stimulated CAR-T cells and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate an ∼10,000-member library of TF combinations. Non-viral KI of a combined BATF-TFAP4 polycistronic construct enhanced fitness. Overexpressed BATF and TFAP4 co-occupy and regulate key gene targets to reprogram T cell function. ModPoKI facilitates the discovery of complex gene constructs to program cellular functions.


Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Ejercicio Físico , Humanos , Biblioteca de Genes , Inmunoterapia , Investigación
2.
Nature ; 609(7925): 174-182, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36002574

RESUMEN

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.


Asunto(s)
Antígenos de Neoplasias , Neoplasias , Linfocitos T , Proteínas Activadoras de ras GTPasa , Animales , Antígenos de Neoplasias/inmunología , Médula Ósea , Sistemas CRISPR-Cas , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Inmunoterapia Adoptiva , Leucemia/inmunología , Leucemia/patología , Leucemia/terapia , Ratones , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factores de Tiempo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Activadoras de ras GTPasa/deficiencia , Proteínas Activadoras de ras GTPasa/genética
3.
Haematologica ; 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38356450

RESUMEN

The ongoing development of immunotherapies, including chimeric antigen receptor (CAR) T cells, has revolutionized cancer treatment. In paediatric relapsed/refractory B-lineage acute leukaemia antiCD19-CARs induced impressive initial response rates, with event-free survival plateauing at 30-50% in long-term follow-up data. During the interval between diagnosis of relapse or refractoriness and CAR T cell infusion, patients require a bridging therapy. To date, this therapy has consisted of highly variable approaches based on local experience. Here, in an European collaborative effort of paediatric and adult haematologists, we summarise current knowledge with the aim of establishing a guidance for bridging therapy. This includes treatment strategies for different patient subgroups, the advantages and disadvantages of low- and highintensity regimens, and the potential impact of bridging therapy on outcome after CAR T cell infusion. This guidance is a step towards a cross-institutional harmonization of bridging therapy, including personalized approaches. This will allow better comparability of clinical data and increase the level of evidence for the treatment of children and young adults with relapsed/refractory B-lineage ALL until CAR T cell infusion.

4.
Pediatr Hematol Oncol ; 41(7): 504-518, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39235390

RESUMEN

The COVID-19 pandemic affected daily life significantly and had massive consequences for healthcare systems with tremendous regional differences. This retrospective study aimed to investigate whether the pandemic and resulting societal changes impacted the diagnosis of pediatric malignancies in a distinct region. Pediatric cancer cases in Bavaria (2016-2021) and SARS-CoV-2 proceedings during the peak phase of the pandemic (2020-2021) were retrospectively analyzed. All new diagnoses of pediatric malignancies reported from cancer centers in Bavaria were included. Clinical data from pre-pandemic years was compared to diagnoses made during the pandemic. Official SARS-CoV-2 reports were received from the Bavarian Health and Food Safety Authority and data on regional pandemic measures were obtained from the Healthcare Data Platform. With this design, a comprehensive analysis of the pandemic proceedings was performed. We found significantly decreased incidence-rate ratios for pediatric cancer diagnosis during the early spring peak of SARS-CoV-2 as it was observed in May during the pandemic, followed by non-significantly increased metastatic cancer diagnosis two months later. Additionally, the time-to-diagnosis of pediatric malignancies was significantly prolonged during the pandemic, and outpatient contacts were significantly reduced, although the availability of consultations remained the same. From our findings, we may hypothesize that there have been effects on pediatric cancer diagnosis during the COVID-19 pandemic at vulnerable times. Interpretation of changes remains speculative with potential causes from behavior patterns, such as hesitation, concerns, and potential societal changes during phases of public restrictions, rather than overwhelmed medical capacities. Nevertheless, specific awareness is needed to protect this patient population during potential future pandemics.


Asunto(s)
COVID-19 , Neoplasias , Pandemias , SARS-CoV-2 , Humanos , COVID-19/epidemiología , Niño , Estudios Retrospectivos , Neoplasias/epidemiología , Neoplasias/diagnóstico , Alemania/epidemiología , Femenino , Masculino , Preescolar , Adolescente , Lactante , Incidencia
5.
HNO ; 72(6): 423-439, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38214716

RESUMEN

BACKGROUND: Treatment of Epstein-Barr virus(EBV)-positive nasopharyngeal carcinoma (NPC) with cisplatin/5-fluorouracil (5-FU) induction chemotherapy, followed by radiochemotherapy and subsequent interferon­ß, has yielded high survival rates in children, adolescents, and young adults. A previous study has shown that reduction of radiation dose from 59.4 to 54.0 Gy appears to be safe in patients with complete response (CR) to induction chemotherapy. As immune checkpoint-inhibitors have shown activity in NPC, we hypothesize that the addition of nivolumab to standard induction chemotherapy would increase the rate of complete tumor responses, thus allowing for a reduced radiation dose in a greater proportion of patients. METHODS: This is a prospective multicenter phase 2 clinical trial including pediatric and adult patients with their first diagnosis of EBV-positive NPC, scheduled to receive nivolumab in addition to standard induction chemotherapy. In cases of non-response to induction therapy (stable or progressive disease), and in patients with initial distant metastasis, treatment with nivolumab will be continued during radiochemotherapy. Primary endpoint is tumor response on magnetic resonance imaging (MRI) and positron emission tomography (PET) after three cycles of induction chemotherapy. Secondary endpoints are event-free (EFS) and overall survival (OS), safety, and correlation of tumor response with programmed cell death ligand 1 (PD-L1) expression. DISCUSSION: As cure rates in localized EBV-positive NPC today are high with standard multimodal treatment, the focus increasingly shifts toward prevention of late effects, the burden of which is exceptionally high, mainly due to intense radiotherapy. Furthermore, survival in patients with metastatic disease and resistant to conventional chemotherapy remains poor. Primary objective of this study is to investigate whether the addition of nivolumab to standard induction chemotherapy in children and adults with EBV-positive NPC is able to increase the rate of complete responses, thus enabling a reduction in radiation dose in more patients, but also offer patients with high risk of treatment failure the chance to benefit from the addition of nivolumab. TRIAL REGISTRATION: EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) No. 2021-006477-32.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia de Inducción , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Nivolumab , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/métodos , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/diagnóstico , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/virología , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/virología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/terapia , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Estudios Prospectivos , Resultado del Tratamiento , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase II como Asunto
6.
Br J Cancer ; 129(4): 696-705, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37400680

RESUMEN

BACKGROUND: In many situations, the therapeutic efficacy of CAR T cells is limited due to immune suppression and poor persistence. Immunostimulatory fusion protein (IFP) constructs have been advanced as a tool to convert suppressive signals into stimulation and thus promote the persistence of T cells, but no universal IFP design has been established so far. We now took advantage of a PD-1-CD28 IFP as a clinically relevant structure to define key determinants of IFP activity. METHODS: We compared different PD-1-CD28 IFP variants in a human leukemia model to assess the impact of distinctive design choices on CAR T cell performance in vitro and a xenograft mouse model. RESULTS: We observed that IFP constructs that putatively exceed the extracellular length of PD-1 induce T-cell response without CAR target recognition, rendering them unsuitable for tumour-specific therapy. IFP variants with physiological PD-1 length ameliorated CAR T cell effector function and proliferation in response to PD-L1+ tumour cells in vitro and prolonged survival in vivo. Transmembrane or extracellular CD28 domains were found to be replaceable by corresponding PD-1 domains for in vivo efficacy. CONCLUSION: PD-1-CD28 IFP constructs must mimic the physiological interaction of PD-1 with PD-L1 to retain selectivity and mediate CAR-conditional therapeutic activity.


Asunto(s)
Inmunoterapia Adoptiva , Leucemia , Humanos , Ratones , Animales , Antígenos CD28 , Receptor de Muerte Celular Programada 1 , Antígeno B7-H1 , Línea Celular Tumoral
7.
Cancer Immunol Immunother ; 72(11): 3621-3634, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37610672

RESUMEN

Immune milieus play an important role in various types of cancer. The present study focuses on the effect of Th1 cytokines on pediatric acute lymphoblastic leukemia (ALL). The reaction of ALL cell lines and patient-derived xenografts (PDX) to the most important Th1 cytokines TNF-α (tumor necrosis factor alpha) and IFN-γ (interferon gamma) is analyzed and correlated with the respective cytokine receptors and the intracellular signaling molecules. ALL cell lines and ALL PDX display a great heterogeneity in cell death after incubation with TNF-α and IFN-γ. Several samples show a dose-dependent and additive induction of cell death by both cytokines; others do not react at all or even display an increased viability. Apoptosis is the main type of cell death induced by Th1 cytokines in ALL cells. Over all leukemia cells analyzed, IFN-γ receptor (IFNGR) shows a higher expression than both TNF-receptors, resulting in higher phosphorylation of STAT1 (signal transducer and activator of transcription) compared to phosphorylation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells) in the TNF pathway. The activation of STAT1 correlates with the amount of cell death after stimulation with Th1 cytokines. TNF-α and IFN-γ lead to heterogeneous reactions in ALL cell lines and ALL PDX but are able to induce cell death by apoptosis in the majority of ALL blasts. The correlation of a high expression of IFNGR and following activation of STAT1 with cell death indicates an important role for IFN-γ signaling in this setting.


Asunto(s)
Citocinas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Citocinas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Interferón gamma/metabolismo , Factor de Transcripción STAT1
8.
Blood ; 137(8): 1037-1049, 2021 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-33094319

RESUMEN

Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting, and several suitable immunotargets (HAVCR2/CD33 and HAVCR2/CLEC12A) have been identified in adult AML. However, clinical and biologic characteristics of AML differ between children and the elderly. Here, we analyzed 36 bone marrow (BM) samples of pediatric AML patients and 13 age-matched healthy donors using whole RNA sequencing of sorted CD45dim and CD34+CD38-CD45dim BM populations and flow cytometry for surface expression of putative target antigens. Pediatric AML clusters apart from healthy myeloid BM precursors in principal-component analysis. Known immunotargets of adult AML, such as IL3RA, were not overexpressed in pediatric AML compared with healthy precursors by RNA sequencing. CD33 and CLEC12A were the most upregulated immunotargets on the RNA level and showed the highest surface expression on AML detected by flow cytometry. KMT2A-mutated infant AML clusters separately by RNA sequencing and overexpresses FLT3, and hence, CD33/FLT3 cotargeting is an additional specific option for this subgroup. CLEC12A and CD33/CLEC12Adouble-positive expression was absent in CD34+CD38-CD45RA-CD90+ hematopoietic stem cells (HSCs) and nonhematopoietic tissue, while CD33 and FLT3 are expressed on HSCs. In summary, we show that expression of immunotargets in pediatric AML differs from known expression profiles in adult AML. We identify CLEC12A and CD33 as preferential generic combinatorial immunotargets in pediatric AML and CD33 and FLT3 as immunotargets specific for KMT2A-mutated infant AML.


Asunto(s)
Regulación Leucémica de la Expresión Génica , Lectinas Tipo C/genética , Leucemia Mieloide Aguda/genética , Receptores Mitogénicos/genética , Lectina 3 Similar a Ig de Unión al Ácido Siálico/genética , Adolescente , Niño , Preescolar , Femenino , Humanos , Inmunoterapia , Lactante , Lectinas Tipo C/inmunología , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Masculino , Receptores Mitogénicos/inmunología , Lectina 3 Similar a Ig de Unión al Ácido Siálico/inmunología , Transcriptoma , Regulación hacia Arriba
9.
Haematologica ; 108(8): 2080-2090, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-36794500

RESUMEN

Therapy-resistant viral reactivations contribute significantly to mortality after hematopoietic stem cell transplantation. Adoptive cellular therapy with virus-specific T cells (VST) has shown efficacy in various single-center trials. However, the scalability of this therapy is hampered by laborious production methods. In this study we describe the in-house production of VST in a closed system (CliniMACS Prodigy® system, Miltenyi Biotec). In addition, we report the efficacy in 26 patients with viral disease following hematopoietic stem cell transplantation in a retrospective analysis (adenovirus, n=7; cytomegalovirus, n=8; Epstein-Barr virus, n=4; multi-viral, n=7). The production of VST was successful in 100% of cases. The safety profile of VST therapy was favorable (n=2 grade 3 and n=1 grade 4 adverse events; all three were reversible). A response was seen in 20 of 26 patients (77%). Responding patients had a significantly better overall survival than patients who did not respond (P<0.001). Virus-specific symptoms were reduced or resolved in 47% of patients. The overall survival of the whole cohort was 28% after 6 months. This study shows the feasibility of automated VST production and safety of application. The scalability of the CliniMACS Prodigy® device increases the accessibility of VST treatment.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Virosis , Humanos , Linfocitos T , Infecciones por Virus de Epstein-Barr/terapia , Estudios Retrospectivos , Herpesvirus Humano 4 , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Virosis/etiología , Virosis/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre
10.
Ann Hematol ; 102(11): 3217-3227, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37726493

RESUMEN

Many sickle cell disease (SCD) patients lack matched family donors (MFD) or matched unrelated donors (MUD), implying haploidentical donors (MMFD) as a logical donor choice. We used a reduced toxicity protocol for all donor types. We included 31 patients (2-22 years) with MFD (n = 15), MMFD (10), or MUD (6) HSCT and conditioning with alemtuzumab/ATG, thiotepa, fludarabine and treosulfan, and post-transplant cyclophosphamide for MMFD. After the initial six patients, treosulfan was replaced by targeted busulfan (AUC 65-75 ng*h/ml). After a median follow-up of 26 months (6-123), all patients are alive and off immunosuppression. Two MMFD patients experienced secondary graft failure with recurrence of SCD, both after treosulfan conditioning. Neither acute GVHD ≥ °III nor moderate/severe chronic GVHD was observed. The disease-free, severe GVHD-free survival was 100%, 100%, and 80% in the MFD, MUD, and MMFD groups, respectively (p = 0.106). There was a higher rate of virus reactivation in MMFD (100%) and MUD (83%) compared to MFD (40%; p = 0.005), but not of viral disease (20% vs 33% vs 13%; p = 0.576). Six patients had treosulfan-based conditioning, two of whom experienced graft failure (33%), compared to 0/25 (0%) after busulfan-based conditioning (p = 0.032). Donor chimerism was ≥ 80% in 28/31 patients (90%) at last follow-up. Reduced toxicity myeloablative conditioning resulted in excellent overall survival, negligible GVHD, and low toxicity among all donor groups in pediatric and young adult patients with SCD.

11.
Mol Ther ; 30(1): 198-208, 2022 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-34058386

RESUMEN

Viral infections cause life-threatening disease in immunocompromised patients and especially following transplantation. T cell receptor (TCR) engineering redirects specificity and can bring significant progress to emerging adoptive T cell transfer (ACT) approaches. T cell epitopes are well described, although knowledge is limited on which TCRs mediate protective immunity. In this study, refractory adenovirus (AdV) infection after hematopoietic stem cell transplantation (HSCT) was treated with ACT of highly purified Hexon5-specific T cells using peptide major histocompatibility complex (pMHC)-Streptamers against the immunodominant human leukocyte antigen (HLA)-A∗0101-restricted peptide LTDLGQNLLY. AdV was successfully controlled through this oligoclonal ACT. Novel protective TCRs were isolated ex vivo and preclinically engineered into the TCR locus of allogeneic third-party primary T cells by CRISPR-Cas9-mediated orthotopic TCR replacement. Both TCR knockout and targeted integration of the new TCR in one single engineering step led to physiological expression of the transgenic TCR. Reprogrammed TCR-edited T cells showed strong virus-specific functionality such as cytokine release, effector marker upregulation, and proliferation capacity, as well as cytotoxicity against LTDLGQNLLY-presenting and AdV-infected targets. In conclusion, ex vivo isolated TCRs with clinical proven protection through ACT could be redirected into T cells from naive third-party donors. This approach ensures that transgenic TCRs are protective with potential off-the-shelf use and widened applicability of ACT to various refractory emerging viral infections.


Asunto(s)
Receptores de Antígenos de Linfocitos T , Virosis , Traslado Adoptivo , Humanos , Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T
12.
Blood ; 136(12): 1407-1418, 2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32483603

RESUMEN

Anti-CD19 chimeric antigen receptor (CAR) T cells showed significant antileukemic activity in B-precursor acute lymphoblastic leukemia (ALL). Allogeneic, HLA-mismatched off-the-shelf third-party donors may offer ideal fitness of the effector cells, but carry the risk of graft-versus-host disease. Knockout (KO) of the endogenous T-cell receptor (TCR) in CD19-CAR-T cells may be a promising solution. Here, we induced a CRISPR/Cas9-mediated KO of the TCRß chain in combination with a second-generation retroviral CAR transduction including a 4-1BB costimulatory domain in primary T cells. This tandem engineering led to a highly functional population of TCR-KO-CAR-T cells with strong activation (CD25, interferon γ), proliferation, and specific killing upon CD19 target recognition. TCR-KO-CAR-T cells had a balanced phenotype of central memory and effector memory T cells. KO of the endogenous TCR in T cells strongly ablated alloreactivity in comparison with TCR-expressing T cells. In a patient-derived xenograft model of childhood ALL, TCR-KO-CAR-T cells clearly controlled CD19+ leukemia burden and improved survival in vivo. However, coexpression of endogenous TCR plus CAR led to superior persistence of T cells and significantly prolonged leukemia control in vivo, confirmed by a second in vivo model using the leukemia cell line NALM6. These results point toward an essential role of the endogenous TCR for longevity of the response at the price of alloreactivity. In conclusion, anti-CD19 CAR T cells with a CRISPR/Cas9-mediated TCR-KO are promising candidates for nonmatched third-party adoptive T-cell transfer with high antileukemic functionality in the absence of alloreactivity, but long-term persistence in vivo is better in the presence of the endogenous TCR.


Asunto(s)
Sistemas CRISPR-Cas , Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Receptores de Antígenos de Linfocitos T/genética , Transducción Genética , Células Tumorales Cultivadas
13.
Haematologica ; 107(5): 1026-1033, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-34348455

RESUMEN

Novel treatment strategies are needed to improve cure for all children with acute lymphoblastic leukemia (ALL). To this end, we investigated the therapeutic potential of clofarabine in primary ALL in trial CoALL 08-09 (clinicaltrials gov. identifier: NCT01228331). The primary study objective was the minimal residual disease (MRD)- based comparative assessment of cytotoxic efficacies of clofarabine 5x40 mg/m2 versus high-dose cytarabine (HIDAC) 4x3g/m2, both in combination with PEG-ASP 2,500 IU/m2 as randomized intervention in early consolidation. The secondary objective was an outcome analysis focused on treatment arm dependence and MRD after randomized intervention. In B-cell precursor (BCP)-ALL, eradication of MRD was more profound after clofarabine compared to cytarabine, with 93 versus 79 of 143 randomized patients per arm reaching MRD-negativity (c2 test P=0.03, leftsided P [Fisher's exact test]=0.04). MRD status of BCP-ALL after randomized intervention maintained its prognostic relevance, with a significant impact on event-free survival (EFS) and relapse rate. However, no difference in outcome regarding EFS and overall survival (OS) between randomized courses was observed (5-year EFS: clofarabine 85.7, SE=4.1 vs. HIDAC 84.8, SE=4.7 [P=0.96]; OS: 95.7, SE=1.9 vs. 92.2, SE=3.2 [P=0.59]), independent of covariates or overall risk strata. Severe toxicities between randomized and subsequent treatment elements were also without significant difference. In conclusion, clofarabine/PEG-ASP is effective and safe, but greater cytotoxic efficacy of clofarabine compared to HIDAC did not translate into improved outcomes indicating a lack of surrogacy of post-intervention MRD at the trial level as opposed to the patient level, which hampers a broader implementation of this regimen in the frontline treatment of ALL.


Asunto(s)
Antineoplásicos , Linfoma no Hodgkin , Leucemia-Linfoma Linfoblástico de Células Precursoras , Enfermedad Aguda , Antineoplásicos/uso terapéutico , Niño , Clofarabina , Citarabina/uso terapéutico , Supervivencia sin Enfermedad , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Resultado del Tratamiento
14.
Pediatr Blood Cancer ; 69(12): e29997, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36129234

RESUMEN

BACKGROUND: The prognosis of children with acute lymphoblastic leukemia (ALL) has improved considerably over the past five decades. However, to achieve cure in patients with refractory or relapsed disease, novel treatment options are necessary. METHODS: In the multicenter trial Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (CoALL)08-09, one additional treatment element consisting of the rarely used chemotherapeutic agent amsacrine combined with etoposide and methylprednisolone (AEP) (amsacrine 2 × 100 mg/m2 , etoposide 2 × 500 mg/m2 , and methylprednisolone 4 × 1000 mg/m2 ) was incorporated into the first-line treatment of pediatric patients with poor treatment responses at the end of induction (EOI), measured by minimal residual disease (MRD). These patients were stratified into a high-risk intensified arm (HR-I), including an AEP element at the end of consolidation. Patients with induction failure (IF), that is, with lack of cytomorphological remission EOI, were eligible for hematopoietic stem cell transplantation (HSCT) after remission had been reached. These patients received AEP as a part of their MRD-guided bridging-to-transplant treatments. RESULTS: A significant improvement in probability of overall survival (pOS) was noted for the CoALL08-09 HR-I patients compared to MRD-matched patients from the preceding CoALL07-03 trial in the absence of severe or persistent treatment-related toxicities. Relapse rate and probability of event-free survival (pEFS) did not differ significantly between trials. In patients with IF, stable or improved MRD responses after AEP were observed without severe or persistent treatment-related toxicities. CONCLUSION: In conclusion, AEP is well tolerated as a component of the HR treatment and is useful in bridging-to-transplant settings.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Etopósido , Amsacrina/uso terapéutico , Metilprednisolona , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Neoplasia Residual , Supervivencia sin Enfermedad
15.
Pediatr Transplant ; 26(5): e14285, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35441401

RESUMEN

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for children with both malignant and nonmalignant diseases. T-cell depletion techniques may result in reduced transplant-related mortality compared with unmanipulated grafts due to a lower incidence of GvHD. METHODS: Immune recovery and outcome were analyzed in a cohort of 23 patients with malignant and nonmalignant diseases who received CD3+TCRαß+ T- and B-cell-depleted allografts from matched donors after reduced-intensity or myeloablative conditioning. The median number of CD34+, CD3+TCRαß+, and CD19+B-cells infused was 12.7 × 106 /kg, 16.8 × 103 /kg, and 96 × 103 /kg bodyweight. RESULTS: With a median follow-up of 36 (range 1-73) months, overall survival and disease-free survival at 3 years were 65.2% and 60.8%. Eight patients died, six due to the underlying disease and two of extended visceral cGvHD. Immune reconstitution, disease-free, and overall survivals were similar compared with a historical cohort of 23 patients transplanted with matched unmanipulated bone marrow. A significant lower rate of higher grade (III-IV) aGvHD was observed in the manipulated HSCT group (8.7% vs. 26%; p = 0.001), whereas the incidence of cGvHD was equal. CONCLUSIONS: Our data suggest that this graft manipulation strategy could be a safe and effective alternative to conventional HSCT techniques in matched donors.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Antígenos CD19 , Niño , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Depleción Linfocítica , Receptores de Antígenos de Linfocitos T alfa-beta , Acondicionamiento Pretrasplante/métodos
16.
Eur J Cancer Care (Engl) ; 31(2): e13559, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35150025

RESUMEN

OBJECTIVE: Cancer diagnosis, treatment side effects and physical inactivity can lead to reduced muscle strength. Patients undergoing acute treatment experience many burdens that can restrict their mobility and autonomy, leading to limited independence and loss of resources to cope with everyday tasks. In this work, we analyse the status quo and potential influencing factors for the accomplishment of activities of daily living (ADLs) shortly after cancer diagnosis. METHODS: We recruited participants ages 4-18 years diagnosed with acute leukaemia or non-Hodgkin lymphoma. For the baseline analysis, we assessed (1) physical function limitations using the Activities Scale for Kids©, (2) exercise-related ADLs simulated with the Functional ADL Screen, (3) motor performance using the Motor Performance in Paediatric Oncology test and (4) physical activity (PA) level measured using an accelerometer. RESULTS: We conducted the baseline assessment 19.2 ± 12.6 days post-diagnosis in 41 patients. All participants reported functional limitations in ADLs and PA. Motor performance was reduced for all abilities. Cumulative steroid dose was negatively correlated with hand grip strength (r = -0.50, p = 0.009). CONCLUSION: Shortly after diagnosis of paediatric cancer, patients experience various physical impairments that can be counteracted with regular, instructed exercise interventions.


Asunto(s)
Leucemia , Linfoma no Hodgkin , Neoplasias , Actividades Cotidianas , Adolescente , Niño , Preescolar , Ejercicio Físico , Fuerza de la Mano , Humanos , Leucemia/terapia , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/terapia , Neoplasias/terapia , Autoinforme
17.
Eur J Haematol ; 106(4): 473-483, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33320384

RESUMEN

OBJECTIVE: Pediatric patients with relapsed or refractory acute lymphoblastic leukemia have a poor prognosis. We here assess the response rates, adverse events, and long-term follow-up of pediatric patients with relapsed/refractory acute lymphoblastic leukemia receiving blinatumomab. METHODS: Retrospective analysis of a single-center experience with blinatumomab in 38 patients over a period of 10 years. RESULTS: The median age at onset of therapy was 10 years (1-21 years). Seventy-one percent of patients had undergone at least one hematopoietic stem cell transplantation (HSCT) prior to treatment with blinatumomab. We observed a response to blinatumomab in 13/38 patients (34%). The predominant side effect was febrile reactions, nearly half of the patients developed a cytokine release syndrome. Eight events of neurotoxicity were registered over the 78 cycles (15%). To date, nine patients (24%) are alive and in complete molecular remission. All survivors underwent haploidentical HSCT after treatment with blinatumomab. CONCLUSIONS: Despite heavy pretreatment of most of our patients, severe adverse events were rare and response rates encouraging. Blinatumomab is a valuable bridging salvage therapy for relapsed or refractory patients to a second or even third HSCT.


Asunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Adolescente , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Niño , Preescolar , Terapia Combinada , Manejo de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Pronóstico , Recurrencia , Retratamiento , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
18.
Mol Ther ; 28(9): 1965-1973, 2020 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-32559432

RESUMEN

Immunosuppression posttransplantation exposes patients to an increased risk for refractory viral infections as an important cause of morbidity and mortality. Protective T cell immunity can be restored by adoptive T cell transfer, but ongoing immunosuppression limits efficacy of T cell responses. In order to deliver protection against viral pathogens and allow at the same time necessary steroid therapy, we generated glucocorticoid-resistant T cells by CRISPR-Cas9-mediated knockout of the glucocorticoid receptor in primary human virus-specific T cell products. Characterization of the T cell product revealed high efficiency of glucocorticoid receptor knockout and high purity of virus-specific T cells. This tandem T cell engineering preserved protective T cell functionality, such as cytotoxicity, CD107a degranulation, proliferative capacity, and cytokine release patterns. Virus-specific T cells with glucocorticoid receptor knockout were resistant to the suppressive effect of dexamethasone treatment on lymphocyte proliferation and cytokine secretion (tumor necrosis factor alpha [TNF-α], interleukin-4 [IL-4], IL-6, and sFas). Additionally, glucocorticoid receptor knockout cells remained sensitive to cyclosporine A treatment, thereby providing a rescue approach for patients in case of safety issues. This novel approach provides a therapeutic option for the treatment of patients with viral infections after transplantation who are receiving glucocorticoid therapy.


Asunto(s)
Traslado Adoptivo/métodos , Sistemas CRISPR-Cas , Ingeniería Celular/métodos , Resistencia a Medicamentos/genética , Glucocorticoides/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfocitos T/inmunología , Virosis/etiología , Virosis/terapia , Proliferación Celular/genética , Células Cultivadas , Ciclosporina/farmacología , Citocinas/metabolismo , Técnicas de Inactivación de Genes/métodos , Humanos , Activación de Linfocitos/inmunología , Receptores de Glucocorticoides/deficiencia , Receptores de Glucocorticoides/genética , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Proteínas de la Matriz Viral/inmunología , Virosis/inmunología
19.
Cytotherapy ; 21(9): 973-986, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31351799

RESUMEN

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in childhood and adolescence. Although some patients present with distinct genetic alterations, such as mutated TP53 or MYC amplification, pediatric medulloblastoma is a tumor entity with minimal mutational load and low immunogenicity. METHODS: We identified tumor-specific mutations using next-generation sequencing of medulloblastoma DNA and RNA derived from primary tumor samples from pediatric patients. Tumor-specific mutations were confirmed using deep sequencing and in silico analyses predicted high binding affinity of the neoantigen-derived peptides to the patients' human leukocyte antigen molecules. Tumor-specific peptides were synthesized and used to induce a de novo T-cell response characterized by interferon gamma and tumor necrosis factor alpha release of CD8+ cytotoxic T cells in vitro. RESULTS: Despite low mutational tumor burden, at least two immunogenic tumor-specific peptides were identified in each patient. T cells showed a balanced CD4/CD8 ratio and mostly effector memory phenotype. Induction of a CD8-specific T-cell response was achieved for the neoepitopes derived from Histidine Ammonia-Lyase (HAL), Neuraminidase 2 (NEU2), Proprotein Convertase Subtilisin (PCSK9), Programmed Cell Death 10 (PDCD10), Supervillin (SVIL) and tRNA Splicing Endonuclease Subunit 54 (TSEN54) variants. CONCLUSION: Detection of patient-specific, tumor-derived neoantigens confirms that even in tumors with low mutational load a molecular design of targets for specific T-cell immunotherapy is possible. The identified neoantigens may guide future approaches of adoptive T-cell transfer, transgenic T-cell receptor transfer or tumor vaccination.


Asunto(s)
Antígenos de Neoplasias/inmunología , Inmunoterapia , Meduloblastoma/genética , Meduloblastoma/terapia , Mutación/genética , Linfocitos T/inmunología , Adolescente , Secuencia de Aminoácidos , Niño , Epítopos/inmunología , Femenino , Humanos , Lactante , Masculino , Meduloblastoma/inmunología , Péptidos/química
20.
BMC Cancer ; 19(1): 1118, 2019 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-31730451

RESUMEN

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) belong among the most burdensome side effects in hemato-oncology. Mostly, a combination of ondansetron and dexamethasone is used as antiemetic prophylaxis in pediatric patients undergoing emetogenic chemotherapy. However, dexamethasone is prohibited in different pediatric chemotherapy protocols. Currently, data on the use of ondansetron with the new antiemetic agent fosaprepitant without dexamethasone is not available for pediatric patients. METHODS: In this non-interventional observation study, 79 pediatric patients with a median age of 8.0 years (range 0.5-17.9 years) who received a CINV prophylaxis regimen with either fosaprepitant (4 mg/kg; maximum 150 mg) and ondansetron (as 24-h continuous infusion) (n = 40; fosaprepitant group/FG) or ondansetron only (n = 39; control group/CG) during moderately or highly emetogenic chemotherapy were analyzed. The groups were analyzed and compared for frequency of vomiting, administered doses of on-demand antiemetic dimenhydrinate and adverse events during the acute (0-24 h after chemotherapy administration) and delayed (> 24 h-120 h) CINV phases. RESULTS: A total of 112 and 116 chemotherapy blocks were analyzed in the fosaprepitant and the control group, respectively. The emetogenic potential of the administered chemotherapy did not significantly differ (p = 0.8812) between the two cohorts. In the acute CINV phase, the percentage of patients experiencing vomiting (n = 26 patients) and the vomiting events were significantly higher (p = 0.0005 and p < 0.0001, respectively) in the CG (n = 26 patients (66.7%); 88 events) compared with the FG (n = 10 patients (25.0%); 37 events). In the delayed CINV phase, the percentage of patients experiencing vomiting and the vomiting events were also significantly higher (p = 0.0017 and p < 0.0001, respectively) in the CG (n = 31 patients (79.5%); 164 events) compared with the FG (n = 17 patients (42.5%); 103 events). Additionally, significantly more dimenhydrinate doses were administered in the CG compared with the FG patients (n = 322/n = 198; p < 0.0001). The occurrence of adverse events did not significantly differ between the two groups (p > 0.05). CONCLUSION: Fosaprepitant (4.0 mg/kg) in addition to ondansetron, without application of dexamethasone, was well tolerated, safe, effective and superior to ondansetron only as CINV prophylaxis in pediatric patients during moderately and highly emetogenic chemotherapy.


Asunto(s)
Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Morfolinas/uso terapéutico , Náusea/prevención & control , Neoplasias/tratamiento farmacológico , Vómitos/prevención & control , Adolescente , Antieméticos/efectos adversos , Antineoplásicos/administración & dosificación , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Factibilidad , Femenino , Humanos , Lactante , Masculino , Morfolinas/efectos adversos , Náusea/inducido químicamente , Neoplasias/patología , Ondansetrón/efectos adversos , Ondansetrón/uso terapéutico , Seguridad del Paciente , Resultado del Tratamiento , Vómitos/inducido químicamente
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