RESUMEN
Cancer arises from malignant cells that exist in dynamic multilevel interactions with the host tissue. Cancer therapies aiming to directly kill cancer cells, including oncogene-targeted therapy and immune-checkpoint therapy that revives tumour-reactive cytotoxic T lymphocytes, are effective in some patients1,2, but acquired resistance frequently develops3,4. An alternative therapeutic strategy aims to rectify the host tissue pathology, including abnormalities in the vasculature that foster cancer progression5,6; however, neutralization of proangiogenic factors such as vascular endothelial growth factor A (VEGFA) has had limited clinical benefits7,8. Here, following the finding that transforming growth factor-ß (TGF-ß) suppresses T helper 2 (TH2)-cell-mediated cancer immunity9, we show that blocking TGF-ß signalling in CD4+ T cells remodels the tumour microenvironment and restrains cancer progression. In a mouse model of breast cancer resistant to immune-checkpoint or anti-VEGF therapies10,11, inducible genetic deletion of the TGF-ß receptor II (TGFBR2) in CD4+ T cells suppressed tumour growth. For pharmacological blockade, we engineered a bispecific receptor decoy by attaching the TGF-ß-neutralizing TGFBR2 extracellular domain to ibalizumab, a non-immunosuppressive CD4 antibody12,13, and named it CD4 TGF-ß Trap (4T-Trap). Compared with a non-targeted TGF-ß-Trap, 4T-Trap selectively inhibited TH cell TGF-ß signalling in tumour-draining lymph nodes, causing reorganization of tumour vasculature and cancer cell death, a process dependent on the TH2 cytokine interleukin-4 (IL-4). Notably, the 4T-Trap-induced tumour tissue hypoxia led to increased VEGFA expression. VEGF inhibition enhanced the starvation-triggered cancer cell death and amplified the antitumour effect of 4T-Trap. Thus, targeted TGF-ß signalling blockade in helper T cells elicits an effective tissue-level cancer defence response that can provide a basis for therapies directed towards the cancer environment.
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Neoplasias de la Mama/terapia , Inmunoterapia , Transducción de Señal/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Hipoxia de la Célula , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Interleucina-4/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Masculino , Ratones , Receptor Tipo II de Factor de Crecimiento Transformador beta/química , Receptor Tipo II de Factor de Crecimiento Transformador beta/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Factor de Crecimiento Transformador beta/inmunología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
INTRODUCTION: Data on ovarian function in neuroblastoma survivors are limited. We sought to determine the prevalence of ovarian dysfunction in a cohort of high-risk neuroblastoma survivors and compare outcomes among survivors treated with and without autologous stem cell rescue (ASCR) preceded by myeloablative chemotherapy. METHODS: Retrospective review of female survivors of high-risk neuroblastoma ≥5 years from diagnosis, diagnosed between 1982 and 2014, and followed in a tertiary cancer center. Participants were divided into two groups: individuals treated with conventional chemotherapy ± radiation ("non-ASCR") (n = 32) or with chemotherapy ± radiation followed by myeloablative chemotherapy with ASCR ("ASCR") (n = 51). Ovarian dysfunction was defined as follicle-stimulating hormone ≥15 mU/mL, while premature ovarian insufficiency (POI) was defined as persistent ovarian dysfunction requiring hormone replacement therapy. Poisson models were used to determine prevalence ratios of ovarian dysfunction and POI. RESULTS: Among 83 females (median attained age: 19 years [range, 10-36]; median follow-up: 15 years [range, 7-36]), 49 (59%) had ovarian dysfunction, and 34 (41%) developed POI. Survivors treated with ASCR were 3.2-fold more likely to develop ovarian dysfunction (95% CI: 1.8-6.0; p < 0.001) and 4.5-fold more likely to develop POI (95% CI: 1.7-11.7; p = 0.002) when compared with those treated with conventional chemotherapy, after adjusting for attained age. Two participants in the non-ASCR group and six in the ASCR group achieved at least one spontaneous pregnancy. DISCUSSION: Ovarian dysfunction is prevalent in female high-risk neuroblastoma survivors, especially after ASCR. Longitudinal follow-up of larger cohorts is needed to inform counseling about the risk of impaired ovarian function after neuroblastoma therapy.
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Supervivientes de Cáncer , Neuroblastoma , Insuficiencia Ovárica Primaria , Humanos , Femenino , Neuroblastoma/terapia , Adolescente , Estudios Retrospectivos , Supervivientes de Cáncer/estadística & datos numéricos , Adulto , Niño , Adulto Joven , Insuficiencia Ovárica Primaria/epidemiología , Insuficiencia Ovárica Primaria/etiología , Insuficiencia Ovárica Primaria/inducido químicamente , Estudios de Seguimiento , Ovario/efectos de los fármacos , Ovario/fisiopatología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante AutólogoRESUMEN
Anti-GD2 monoclonal antibodies (mAb) improve the prognosis of high-risk neuroblastoma (HR-NB). Worldwide experience almost exclusively involves toddlers and older patients treated after multimodality or second-line therapies, that is, many months postdiagnosis. In contrast, at our center, infants received anti-GD2 mAbs because this immunotherapy started during or immediately after induction chemotherapy. We now report on the feasibility, safety, and long-term survival in this vulnerable age group. Thirty-three HR-NB patients were <19 months old when started on 3F8 (murine mAb; n = 21) or naxitamab (humanized-3F8; n = 12), with 30â³ to 90â³ intravenous infusions. Patients received analgesics and antihistamines. Common toxicities (pain, urticaria, cough) were manageable, allowing outpatient treatment. Capillary leak, posterior reversible encephalopathy syndrome, and mAb-related long-term toxicities did not occur. Two 3F8 cycles were aborted due to bradycardia (a preexisting condition) and asthmatic symptoms, respectively. One patient received ½ dose of Day 1 naxitamab because of hypotension; full doses were subsequently administered. Post-mAb treatments included chemotherapy, radiotherapy, and anti-NB vaccine. Among 3F8 patients, 17/21 are in complete remission off all treatment at 5.6+ to 24.1+ (median 13.4+) years from diagnosis. Among naxitamab patients, 10/12 remain relapse-free post-mAb at 1.7+ to 4.3+ (median 3.1+) years from diagnosis. Toxicity was similar with short outpatient infusions and matched that observed with these and other anti-GD2 mAbs in older patients. These findings were reassuring given that naxitamab is dosed >2.5× higher (~270 mg/m2 /cycle) than 3F8, dinutuximab, and dinutuximab beta (70-100 mg/m2 /cycle). HR-NB in infants proved to be highly curable.
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Antineoplásicos , Neuroblastoma , Síndrome de Leucoencefalopatía Posterior , Humanos , Lactante , Ratones , Animales , Anciano , Síndrome de Leucoencefalopatía Posterior/inducido químicamente , Síndrome de Leucoencefalopatía Posterior/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Neuroblastoma/tratamiento farmacológico , Inmunoterapia , Factores Inmunológicos/uso terapéutico , Antineoplásicos/uso terapéuticoRESUMEN
Patients with stage 4N neuroblastoma (distant metastases limited to lymph nodes) stand out as virtually the only survivors of high-risk neuroblastoma (HR-NB) before myeloablative therapy (MAT) and immunotherapy with anti-GD2 monoclonal antibodies (mAbs) became standard. Because no report presents more recent results with 4N, we analyzed our large 4N experience. All 51 pediatric 4N patients (<18 years old) diagnosed 1985 to 2021 were reviewed. HR-NB included MYCN-nonamplified 4N diagnosed at age ≥18 months and MYCN-amplified 4N. Among 34 MYCN-nonamplified high-risk patients, 20 are relapse-free 1.5+ to 37.5+ (median 12.5+) years post-diagnosis, including 13 without prior MAT and 5 treated with little (1 cycle; n = 2) or no mAb (n = 3), while 14 patients (7 post-MAT, 8 post-mAbs) relapsed (all soft tissue). Of 15 MYCN-amplified 4N patients, 7 are relapse-free 2.1+ to 26.4+ (median 11.6+) years from the start of chemotherapy (all received mAbs; 3 underwent MAT) and 4 are in second remission 4.2+ to 21.8+ years postrelapse (all soft tissue). Statistical analyses showed no significant association of survival with either MAT or mAbs for MYCN-nonamplified HR-NB; small numbers prevented these analyses for MYCN-amplified patients. The two patients with intermediate-risk 4N (14-months-old) are relapse-free 7+ years postresection of primary tumors; distant disease spontaneously regressed. The natural history of 4N is marked by NB confined to soft tissue without early relapse in bones or bone marrow, where mAbs have proven efficacy. These findings plus curability without MAT, as seen elsewhere and at our center, support consideration of treatment reduction for MYCN-nonamplified 4N.
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Recurrencia Local de Neoplasia , Neuroblastoma , Niño , Humanos , Lactante , Adolescente , Pronóstico , Proteína Proto-Oncogénica N-Myc/genética , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/terapia , Recurrencia Local de Neoplasia/patología , Neuroblastoma/genética , Neuroblastoma/terapia , InmunoterapiaRESUMEN
PURPOSE: Intraventricular compartmental radioimmunotherapy (cRIT) with 131-I-omburtamab is a potential therapy for recurrent primary brain tumors that can seed the thecal space. These patients often previously received external beam radiotherapy (EBRT) to a portion or full craniospinal axis (CSI) as part of upfront therapy. Little is known regarding outcomes after re-irradiation as part of multimodality therapy including cRIT. This study evaluates predictors of response, patterns of failure, and radiologic events after cRIT. METHODS: Patients with recurrent medulloblastoma or ependymoma who received 131-I-omburtamab on a prospective clinical trial were included. Extent of disease at cRIT initiation (no evidence of disease [NED] vs measurable disease [MD]) was assessed as associated with progression-free (PFS) and overall survival (OS) by Kaplan-Meier analysis. RESULTS: All 27 patients (20 medulloblastoma, 7 ependymoma) had EBRT preceding cRIT: most (22, 81%) included CSI (median dose 2340 cGy, boost to 5400 cGy). Twelve (44%) also received EBRT at relapse as bridging to cRIT. There were no cases of radionecrosis. At cRIT initiation, 11 (55%) medulloblastoma and 3 (43%) ependymoma patients were NED, associated with improved PFS (p = 0.002) and OS (p = 0.048) in medulloblastoma. Most relapses were multifocal. With medium follow-up of 3.0 years (95% confidence interval, 1.8-7.4), 6 patients remain alive with NED. CONCLUSION: For patients with medulloblastoma, remission at time of cRIT was associated with significantly improved survival outcomes. Relapses are often multifocal, particularly in the setting of measurable disease at cRIT initiation. EBRT is a promising tool to achieve NED status at cRIT initiation, with no cases of radiation necrosis.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Ependimoma , Meduloblastoma , Humanos , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Encefálicas/radioterapia , Neoplasias Cerebelosas/radioterapia , Enfermedad Crónica , Ependimoma/radioterapia , Radioisótopos de Yodo/uso terapéutico , Meduloblastoma/terapia , Recurrencia Local de Neoplasia/radioterapia , Estudios Prospectivos , Dosificación RadioterapéuticaRESUMEN
BACKGROUND: In high-risk neuroblastoma, multimodality therapy including craniospinal irradiation (CSI) is effective for central nervous system (CNS) relapse. Management of post-CSI CNS relapse is not clearly defined. PROCEDURE: Pediatric patients with neuroblastoma treated with CSI between 2000 and 2019 were identified. Treatment of initial CNS disease (e.g., CSI, intraventricular compartmental radioimmunotherapy [cRIT] with 131 I-monoclonal antibodies targeting GD2 or B7H3) and management of post-CSI CNS relapse ("second CNS relapse") were characterized. Cox proportional hazards models to evaluate factors associated with third CNS relapse and overall survival (OS) were used. RESULTS: Of 128 patients (65% male, median age 4 years), 19 (15%) received CSI with protons and 115 (90%) had a boost. Most (103, 81%) received cRIT, associated with improved OS (hazard ratio [HR] 0.3, 95% confidence interval [CI]: 0.1-0.5, p < .001). Forty (31%) developed a second CNS relapse, associated with worse OS (1-year OS 32.5%, 95% CI: 19-47; HR 3.8; 95% CI: 2.4-6.0, p < .001), and more likely if the leptomeninges were initially involved (HR 2.5, 95% CI: 1.3-4.9, p = .006). Median time to second CNS relapse was 6.8 months and 51% occurred outside the CSI boost field. Twenty-five (63%) patients underwent reirradiation, most peri-operatively (18, 45%) with focal hypofractionation. Eight (20%) patients with second CNS relapse received cRIT, associated with improved OS (HR 0.1; 95% CI: 0.1-0.4, p < .001). CONCLUSIONS: CNS relapse after CSI for neuroblastoma portends a poor prognosis. Surgery with hypofractionated radiotherapy was the most common treatment. Acknowledging the potential for selection bias, receipt of cRIT both at first and second CNS relapse was associated with improved survival. This finding necessitates further investigation.
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Recurrencia Local de Neoplasia , Neuroblastoma , Niño , Humanos , Masculino , Preescolar , Femenino , Recurrencia Local de Neoplasia/terapia , Terapia Combinada , Radioinmunoterapia , Sistema Nervioso Central , Neuroblastoma/radioterapiaRESUMEN
Human CMV (HCMV) is a ubiquitous pathogen that indelibly shapes the NK cell repertoire. Using transcriptomic, epigenomic, and proteomic approaches to evaluate peripheral blood NK cells from healthy human volunteers, we find that prior HCMV infection promotes NK cells with a T cell-like gene profile, including the canonical markers CD3ε, CD5, and CD8ß, as well as the T cell lineage-commitment transcription factor Bcl11b. Although Bcl11b expression is upregulated during NK maturation from CD56bright to CD56dim, we find a Bcl11b-mediated signature at the protein level for FcεRIγ, PLZF, IL-2Rß, CD3γ, CD3δ, and CD3ε in later-stage, HCMV-induced NK cells. BCL11B is targeted by Notch signaling in T cell development, and culture of NK cells with Notch ligand increases cytoplasmic CD3ε expression. The Bcl11b-mediated gain of CD3ε, physically associated with CD16 signaling molecules Lck and CD247 in NK cells is correlated with increased Ab-dependent effector function, including against HCMV-infected cells, identifying a potential mechanism for their prevalence in HCMV-infected individuals and their prospective clinical use in Ab-based therapies.
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Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Infecciones por Citomegalovirus/inmunología , Células Asesinas Naturales/inmunología , Subgrupos Linfocitarios/inmunología , Proteínas Represoras/inmunología , Proteínas Supresoras de Tumor/inmunología , Animales , Complejo CD3/inmunología , Humanos , Ratones , Ratones Transgénicos , TranscriptomaRESUMEN
The cure rate for metastatic or relapsed osteosarcoma has not substantially improved over the past decades despite the exploitation of multimodal treatment approaches, allowing long-term survival in less than 30% of cases. Patients with osteosarcoma often develop resistance to chemotherapeutic agents, where personalized targeted therapies should offer new hope. T cell immunotherapy as a complementary or alternative treatment modality is advancing rapidly in general, but its potential against osteosarcoma remains largely unexplored. Strategies incorporating immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) modified T cells, and T cell engaging bispecific antibodies (BsAbs) are being explored to tackle relapsed or refractory osteosarcoma. However, osteosarcoma is an inherently heterogeneous tumor, both at the intra- and inter-tumor level, with no identical driver mutations. It has a pro-tumoral microenvironment, where bone cells, stromal cells, neovasculature, suppressive immune cells, and a mineralized extracellular matrix (ECM) combine to derail T cell infiltration and its anti-tumor function. To realize the potential of T cell immunotherapy in osteosarcoma, an integrated approach targeting this complex ecosystem needs smart planning and execution. Herein, we review the current status of T cell immunotherapies for osteosarcoma, summarize the challenges encountered, and explore combination strategies to overcome these hurdles, with the ultimate goal of curing osteosarcoma with less acute and long-term side effects.
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Neoplasias Óseas , Osteosarcoma , Humanos , Linfocitos T , Ecosistema , Recurrencia Local de Neoplasia , Inmunoterapia , Osteosarcoma/genética , Neoplasias Óseas/genética , Microambiente Tumoral , Inmunoterapia AdoptivaRESUMEN
Twelvepatients without therapy-related leukemia were studied after completing TOP2 poison chemotherapy in a high-risk neuroblastoma regimen. One patient harbored an inv(11) that was a KMT2A rearrangement. The KMT2A-MAML2 transcript was expressed at low level. The patient was prospectively followed. The inv(11) was undetectable in ensuing samples. Leukemia never developed after a 12.8-year follow-up period. Enriched etoposide-induced TOP2A cleavage in the relevant MAML2 genomic region supports a TOP2A DNA damage mechanism. After completing TOP2 poison chemotherapies, covert KMT2A-R clones may occur in a small minority of patients; however, not all KMT2A rearrangements herald a therapy-related leukemia diagnosis.
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N-Metiltransferasa de Histona-Lisina , Leucemia , Proteína de la Leucemia Mieloide-Linfoide , Neuroblastoma , Transactivadores , Etopósido/administración & dosificación , Estudios de Seguimiento , Reordenamiento Génico , Humanos , Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Factores de Transcripción/genéticaRESUMEN
Pretargeted imaging and radioimmunotherapy approaches are designed to have superior targeting properties over directly targeted antibodies but impose more complex pharmacology, which hinders efforts to optimize the ligands prior to human applications. Human embryonic kidney 293T cells expressing the humanized single-chain variable fragment (scFv) C825 (huC825) with high-affinity for DOTA-haptens (293T-huC825) in a transmembrane-anchored format eliminated the requirement to use other pretargeting reagents and provided a simplified, accelerated assay of radiohapten capture while offering normalized cell surface expression of the molecular target of interest. Using binding assays, ex vivo biodistribution, and in vivo imaging, we demonstrated that radiohaptens based on benzyl-DOTA and a second generation "Proteus" DOTA-platform effectively and specifically engaged membrane-bound huC825, achieving favorable tumor-to-normal tissue uptake ratios in mice. Furthermore, [86Y]Y-DOTA-Bn predicted absorbed dose to critical organs with reasonable accuracy for both [177Lu]Lu-DOTA-Bn and [225Ac]Ac-Pr, which highlights the benefit of a dosimetry-based treatment approach.
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Ingeniería Celular , Haptenos , Radioinmunoterapia/métodos , Radiofármacos/química , Animales , Autorradiografía , Células HEK293 , Humanos , Ratones , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody 131I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya 131I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases. METHODS: Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of 131I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [CIAR(t)], (b) the AUC of the unbound "harmful" antibody, AUC [CIA(t)], and (c) the therapeutic index, AUC [CIAR(t)] ÷ AUC [CIA(t)]. RESULTS: The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of 131I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [CIA(t)]) was predicted to increase more quickly than AUC [CIAR(t)] as a function of 131I-omburtamab dose, but the balance of therapeutic index and AUC [CIAR(t)] remained favorable over a broad range of administered doses (0.48-1.40 mg or 881-2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%. CONCLUSION: The 2-compartmental pharmacokinetic model when applied to intraOmmaya 131I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT00089245.
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Radioisótopos de Yodo , Radioinmunoterapia , Anticuerpos Monoclonales de Origen Murino , Humanos , Radioisótopos de Yodo/uso terapéutico , Índice TerapéuticoRESUMEN
BACKGROUND: Humanized 3F8-bispecific antibody (hu3F8-BsAb) using the IgG(L)-scFv format (where scFv is single-chain variable fragment), where the anti-CD3 huOKT3 scFv is fused with the carboxyl end of the hu3F8 light chain, has potent antitumor cytotoxicity against GD2(+) tumors. To overcome the insufficient number and function of T cells in cancer patients, they can be rejuvenated and expanded ex vivo before arming with hu3F8-BsAb for adoptive transfer, potentially reducing toxic side effects from direct BsAb administration. PROCEDURE: T cells from normal volunteers were expanded and activated ex vivo using CD3/CD28 beads for 8 days. Activated T cells (ATCs) were harvested and co-incubated with a Good Manufacturing Practice grade hu3F8-BsAb at room temperature for 20 min. These armed ATCs were tested for cytotoxicity in vitro and in vivo against human GD2(+) cell lines and patient-derived xenografts in BALB-Rag2-/- IL-2R-γc-KO mice. RESULTS: Hu3F8-BsAb armed ATCs showed robust antigen-specific tumor cytotoxicity against GD2(+) tumors in vitro. In vivo, T cells armed with hu3F8-BsAb were highly cytotoxic against GD2(+) melanoma and neuroblastoma xenografts in mice, accompanied by T-cell infiltration without significant side effects. Only zeptomole (10-21 ) quantities of BsAb per T cell was required for maximal antitumor effects. Tumor response was a function of T-cell dose. CONCLUSION: BsAb armed T cells may have clinical utility as the next generation of cytotherapy combined with recombinant BsAb against human tumors for both adult and pediatrics, if autologous T cells can be activated and expanded ex vivo.
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Linfocitos T , Animales , Anticuerpos Biespecíficos , Anticuerpos Monoclonales Humanizados , Niño , Glucolípidos , Humanos , Melanoma , Ratones , NeuroblastomaRESUMEN
Gangliosides have been considered to modulate cell signals in the microdomain of the cell membrane, lipid/rafts, or glycolipid-enriched microdomain/rafts (GEM/rafts). In particular, cancer-associated gangliosides were reported to enhance the malignant properties of cancer cells. In fact, GD2-positive (GD2+) cells showed increased proliferation, invasion, and adhesion, compared with GD2-negative (GD2-) cells. However, the precise mechanisms by which gangliosides regulate cell signaling in GEM/rafts are not well understood. In order to analyze the roles of ganglioside GD2 in the malignant properties of melanoma cells, we searched for GD2-associating molecules on the cell membrane using the enzyme-mediated activation of radical sources combined with mass spectrometry, and integrin ß1 was identified as a representative GD2-associating molecule. Then, we showed the physical association of GD2 and integrin ß1 by immunoprecipitation/immunoblotting. Close localization was also shown by immuno-cytostaining and the proximity ligation assay. During cell adhesion, GD2+ cells showed multiple phospho-tyrosine bands, i.e., the epithelial growth factor receptor and focal adhesion kinase. The knockdown of integrin ß1 revealed that the increased malignant phenotypes in GD2+ cells were clearly cancelled. Furthermore, the phosphor-tyrosine bands detected during the adhesion of GD2+ cells almost completely disappeared after the knockdown of integrin ß1. Finally, immunoblotting to examine the intracellular distribution of integrins during cell adhesion revealed that large amounts of integrin ß1 were localized in GEM/raft fractions in GD2+ cells before and just after cell adhesion, with the majority being localized in the non-raft fractions in GD2- cells. All these results suggest that GD2 and integrin ß1 cooperate in GEM/rafts, leading to enhanced malignant phenotypes of melanomas.
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Gangliósidos/metabolismo , Integrinas/metabolismo , Melanoma/patología , Animales , Anticuerpos Monoclonales/farmacología , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colágeno Tipo I/metabolismo , Gangliósidos/inmunología , Humanos , Integrina beta1/metabolismo , Espectrometría de Masas , Microdominios de Membrana/metabolismo , Ratones , Fenotipo , Fosfotirosina/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Clearing agents (CAs) can rapidly remove nonlocalized targeting biomolecules from circulation for hepatic catabolism, thereby enhancing the therapeutic index (TI), especially for blood (marrow), of the subsequently administered radioisotope in any multistep pretargeting strategy. Herein we describe the synthesis and in vivo evaluation of a fully synthetic glycodendrimer-based CA for DOTA-based pretargeted radioimmunotherapy (DOTA-PRIT). The novel dendron-CA consists of a nonradioactive yttrium-DOTA-Bn molecule attached via a linker to a glycodendron displaying 16 terminal α-thio-N-acetylgalactosamine (α-SGalNAc) units (CCA α-16-DOTA-Y3+; molecular weight: 9059 Da). Pretargeting [177Lu]LuDOTA-Bn with CCA α-16-DOTA-Y3+ to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [177Lu]LuDOTA-Bn for blood, tumor, liver, spleen, and kidneys of 11.7, 468, 9.97, 5.49, and 13.3 cGy/MBq, respectively. Tumor-to-normal tissues absorbed-dose ratios (i.e., TIs) ranged from 40 (e.g., for blood and kidney) to about 550 for stomach.
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Acetilgalactosamina/química , Dendrímeros/química , Haptenos/metabolismo , Compuestos Heterocíclicos con 1 Anillo/química , Inmunoconjugados/química , Inmunoconjugados/uso terapéutico , Radioinmunoterapia/métodos , Animales , Biotina/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Humanos , Inmunoconjugados/metabolismo , Inmunoconjugados/farmacocinética , Ratones , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: In patients with high-risk neuroblastoma, there is an increased recognition of relapse in the central nervous system (CNS). Craniospinal irradiation (CSI) has been an effective treatment but carries significant long-term complications. It is unclear whether reducing the CSI dose from 21 to 18 Gy can achieve similar CNS tumor control. PATIENTS AND METHODS: A retrospective review of pediatric patients with CNS-relapsed neuroblastoma treated with CSI and boost to parenchymal lesions between 2003 and 2019 was performed. The goal was to assess CNS control comparing 18 Gy and 21 Gy regimens. RESULTS: Ninety-four patients with CNS-relapsed neuroblastoma were treated with CSI followed by intraventricular compartmental radioimmunotherapy. Median age at the time of CNS disease was 4 years (range 1-13 years). Forty-one patients (44%) received 21 Gy CSI prior to an institutional decision to lower the dose; 53 patients (56%) received 18 Gy CSI. Seventy-nine patients (84%) received additional boosts. With a median follow up of 4.1 years for surviving patients, 2-year CNS relapse-free survival was 74% for 18 Gy group versus 77% for 21 Gy group, and 5-year CNS relapse-free survival was 66% for 18 Gy versus 72% for 21 Gy group, respectively (P = .40). Five-year overall survival rate was 43% in 18 Gy group versus 47% in 21 Gy group (P = .72). CONCLUSION: For patients with CNS-relapsed neuroblastoma, CNS disease control is comparable between 18 Gy and 21 Gy CSI dose regimens, in conjunction with radioimmunotherapy and CNS penetrating chemotherapy. More than 65% of the patients remain CNS disease free after 5 years. The findings support 18 Gy as the new standard CSI dose for CNS-relapsed neuroblastoma.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Irradiación Craneoespinal/métodos , Neuroblastoma/radioterapia , Radioinmunoterapia/métodos , Adolescente , Neoplasias Encefálicas/secundario , Niño , Preescolar , Terapia Combinada , Irradiación Craneoespinal/efectos adversos , Femenino , Humanos , Lactante , Masculino , Terapia de Protones/métodos , Dosificación Radioterapéutica , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: We explored the use of intraventricular 131I-Omburtamab targeting B7-H3 in patients with ETMR. METHODS: Patients were enrolled in an IRB approved, phase 1, 3 + 3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3 were eligible. We report on a cohort of three patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi 131I-Omburtamab as a tracer followed by one or two therapeutic 131I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after 131I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 months after therapy (2 years after diagnosis). CONCLUSIONS: 131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Neoplasias del Sistema Nervioso Central/radioterapia , Radioisótopos de Yodo/uso terapéutico , Neoplasias de Células Germinales y Embrionarias/radioterapia , Anticuerpos Monoclonales/líquido cefalorraquídeo , Anticuerpos Monoclonales de Origen Murino/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Preescolar , Resultado Fatal , Femenino , Humanos , Lactante , Inyecciones Intraventriculares , Radioisótopos de Yodo/líquido cefalorraquídeo , Masculino , Neoplasias de Células Germinales y Embrionarias/líquido cefalorraquídeo , Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Radioinmunoterapia , Radiometría , Médula Espinal/diagnóstico por imagenRESUMEN
BACKGROUND/OBJECTIVES: Survivors of high-risk neuroblastoma (NB) are exposed to multimodality therapies early in life and confront late therapy-related toxicities. This study assessed respiratory symptoms, exercise capacity, and longitudinal changes in pulmonary function tests (PFTs) among survivors. DESIGN/METHODS: Survivors of high-risk NB followed in the long-term follow-up clinic at Memorial Sloan Kettering Cancer Center were enrolled. Symptom and physical activity questionnaires were completed. Medical records were reviewed for treatments and comorbidities. Participants completed spirometry, plethysmography, diffusion capacity of the lung for carbon monoxide, 6-minute walk tests (6MWTs), and cardiopulmonary exercise testing. Questionnaires and PFTs were repeated at least one year after enrollment. RESULTS: Sixty-two survivors participated (median age at study: 10.92 years; median age at diagnosis: 2.75 years; median time since completion of therapy: 5.29 years). Thirty-two percent had chronic respiratory symptoms. Seventy-seven percent had PFT abnormalities, mostly mild to moderate severity. Thirty-three completed 6MWTs (median, 634.3 meters); eight completed cardiopulmonary exercise tests (mean VO2 max: 63% predicted); 23 completed a second PFT revealing declines over a median 2.97 years (mean percent predicted forced vital capacity: 79.9 to 70.0; mean forced expiratory volume in 1 second: 81.6 to 69.9). Risks for abnormalities included thoracic surgery, chest radiation therapy (RT), thoracic surgery plus chest RT, and hematopoietic stem cell transplant. CONCLUSIONS: In this cohort of survivors of high-risk NB, PFT abnormalities were common but mostly mild or moderate. Maximal exercise capacity may be affected by respiratory limitations and declines in lung function may occur over time. Continued pulmonary surveillance of this at-risk population is warranted.
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Supervivientes de Cáncer , Tolerancia al Ejercicio , Pulmón/fisiopatología , Neuroblastoma/terapia , Adolescente , Supervivientes de Cáncer/estadística & datos numéricos , Niño , Terapia Combinada/efectos adversos , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Trastornos Respiratorios/diagnóstico , Trastornos Respiratorios/epidemiología , Trastornos Respiratorios/etiología , Pruebas de Función Respiratoria , Riesgo , Fumar/efectos adversos , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Diffuse intrinsic pontine glioma is one of the deadliest central nervous system tumours of childhood, with a median overall survival of less than 12 months. Convection-enhanced delivery has been proposed as a means to efficiently deliver therapeutic agents directly into the brainstem while minimising systemic exposure and associated toxic effects. We did this study to evaluate the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen in children with diffuse intrinsic pontine glioma. METHODS: We did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients were aged 3-21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Karnofsky (patients ≥16 years) performance score of at least 50 at study entry; a minimum weight of 8 kg; and had completed external beam radiation therapy (54·0-59·4 Gy at 1·8 Gy per fraction over 30-33 fractions) at least 4 weeks but no more than 14 weeks before enrolment. Seven dose-escalation cohorts were planned based on standard 3â+â3 rules: patients received a single infusion of 9·25, 18·5, 27·75, 37, 92·5, 120·25, or 148 MBq, respectively, at a concentration of about 37 MBq/mL by convection-enhanced delivery of the radiolabelled antibody [124I]-8H9. The primary endpoint was identification of the maximum tolerated dose. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full planned dose of treatment), and all patients who received any dose of study treatment were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01502917, and is ongoing with an expanded cohort. FINDINGS: From April 5, 2012, to Oct 8, 2016, 28 children were enrolled and treated in the trial, of whom 25 were evaluable for the primary endpoint. The maximum tolerated dose was not reached as no dose-limiting toxicities were observed. One (4%) of 28 patients had treatment-related transient grade 3 hemiparesis and one (4%) had grade 3 skin infection. No treatment-related grade 4 adverse events or deaths occurred. Estimated volumes of distribution (Vd) were linearly dependent on volumes of infusion (Vi) and ranged from 1·5 to 20·1 cm3, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq 124I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200. INTERPRETATION: Convection-enhanced delivery in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be a rational and safe therapeutic strategy. PET-based dosimetry of the radiolabelled antibody [124I]-8H9 validated the principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure. This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma. FUNDING: National Institutes of Health, The Dana Foundation, The Cure Starts Now, Solving Kids' Cancer, The Lyla Nsouli Foundation, Cookies for Kids' Cancer, The Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center.
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Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Glioma/tratamiento farmacológico , Radioinmunoterapia/métodos , Anticuerpos Monoclonales de Origen Murino , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intraventriculares , Radioisótopos de Yodo/administración & dosificación , MasculinoRESUMEN
Adult-onset neuroblastoma is rare and little is known about its biology and clinical course. There is no established therapy for adult-onset neuroblastoma. Anti-GD2 immunotherapy is now standard therapy in children with high-risk neuroblastoma; however, its use has not been reported in adults. Forty-four adults (18-71 years old) diagnosed with neuroblastoma between 1979 and 2015 were treated at Memorial Sloan Kettering Cancer Center. Five, 1, 5 and 33 patients had INSS stage 1, 2, 3 and 4 diseases, respectively. Genetic abnormalities included somatic ATRX (58%) and ALK mutations (42%) but not MYCN-amplification. In the 11 patients with locoregional disease, 10-year progression-free (PFS) and overall survival (OS) was 35.4 ± 16.1% and 61.4 ± 15.3%, respectively. Among 33 adults with stage 4 neuroblastoma, 7 (21%) achieved complete response (CR) after induction chemotherapy and/or surgery. Seven patients with primary refractory neuroblastoma (all with osteomedullary but no soft tissue disease) received anti-GD2 antibodies, mouse or humanized 3F8. Antibody-related adverse events were similar to those in children, response rate being 71.4%. In patients with stage 4 disease at diagnosis, 5-year PFS was 9.7± 5.3% and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years, 10-year OS being only 19.0 ± 8.2%. Patients who achieved CR after induction had superior PFS and OS (p = 0.006, p = 0.031, respectively). Adult-onset neuroblastoma appeared to have different biology from pediatric or adolescent NB, and poorer outcome. Complete disease control appeared to improve long-term survival. Anti-GD2 immunotherapy was well tolerated and might be beneficial.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Gangliósidos/inmunología , Inmunoglobulina G/uso terapéutico , Inmunoterapia , Recurrencia Local de Neoplasia/terapia , Neuroblastoma/terapia , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Neuroblastoma/inmunología , Neuroblastoma/patología , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Locoregional failure is common after subtotal resection in high-risk neuroblastoma. Although a dose of 21 Gy radiation therapy (RT) is standard for treatment of high-risk neuroblastoma after gross total resection, the dose needed for local control of patients with gross residual disease at the time of RT is unknown. We sought to evaluate local control after 21-36 Gy RT in patients with high-risk neuroblastoma undergoing subtotal resection. METHODS: All patients with high-risk neuroblastoma who received RT to their primary site from 2000 to 2016 were reviewed. Of the 331 patients who received consolidative RT to their primary site, 19 (5.7%) underwent subtotal resection and were included in our analysis. Local failure (LF) was correlated with biologic prognostic factors and dose of RT. RESULTS: Median follow-up among surviving patients was 6.0 years. Median RT dose was 25 Gy (range, 21 Gy-36 Gy). The 5-year cumulative incidence of LF among all patients was 17.2%. LF at 5 years was 30% in those who received <30 Gy versus 0% in those who received 30-36 Gy (P = 0.12). There was a trend towards improved local control in patients with tumor size ≤10 cm at diagnosis (P = 0.12). The 5-year event-free and overall survival were 44.9% and 68.7%, respectively. CONCLUSION: After subtotal resection, patients who received less than 30 Gy had poor local control. Doses of 30-36 Gy are likely needed for optimal control of gross residual disease at the time of consolidative RT in high-risk neuroblastoma.