RESUMEN
Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells.
Asunto(s)
Gangliósidos , Inmunidad Innata , Inmunoterapia Adoptiva , Células Asesinas Naturales , Neuroblastoma , Receptores Quiméricos de Antígenos , Linfocitos T , Neuroblastoma/inmunología , Neuroblastoma/terapia , Neuroblastoma/patología , Animales , Humanos , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Ratones , Gangliósidos/inmunología , Línea Celular Tumoral , Inmunoterapia Adoptiva/métodos , Células Asesinas Naturales/inmunología , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Glipicanos/inmunología , Glipicanos/metabolismo , Microambiente Tumoral/inmunología , FemeninoRESUMEN
Background: Patients suffering from neurological symptoms after COVID-19 vaccination (post-COVID-19 vaccination syndrome (PCVS)) have imposed an increasing challenge on medical practice, as diagnostic precision and therapeutic options are lacking. Underlying autoimmune dysfunctions, including autoantibodies, have been discussed in neurological disorders after SARS-CoV-2 infection and vaccination. Here, we describe the frequency and targets of autoantibodies against peripheral nervous system tissues in PCVS. Methods: Sera from 50 PCVS patients with peripheral neurological symptoms after COVID-19 vaccination and 35 vaccinated healthy controls were used in this study. IgG autoreactivity was measured via indirect immunofluorescence assays on mouse sciatic nerve teased fibers. The frequencies of autoantibodies were compared between groups using Fisher's exact test. Serum anti-ganglioside antibodies were measured in ganglioside blots. Autoantibody target identification was performed using immunoprecipitation coupled to mass spectrometry. Subsequent target confirmation was conducted via cell-based assays and ELISA. Results: Compared with controls, PCVS patients had a significantly greater frequency of autoantibodies against peripheral nervous system structures (9/50(18%) vs 1/35(3%); p=0.04). Autoantibodies bound to paranodes (n=5), axons (n=4), Schmidt-Lanterman incisures (n=2) and Schwann cell nuclei (n=1). Conversely, antibodies against gangliosides were absent in PCVS patients. Target identification and subsequent confirmation revealed various subunits of neurofilaments as well as DFS-70 as autoantibody epitopes. Conclusion: Our data suggest that autoantibodies against nervous system tissue could be relevant in PCVS patients. Autoantibodies against neurofilaments and cell nuclei with so far non-established links to this disease spectrum should be further elucidated to determine their biomarker potential.
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Autoanticuerpos , Vacunas contra la COVID-19 , COVID-19 , Inmunoglobulina G , SARS-CoV-2 , Humanos , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Masculino , Femenino , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Persona de Mediana Edad , COVID-19/inmunología , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Anciano , Ratones , Animales , Adulto , Vacunación , Gangliósidos/inmunología , Nervios Periféricos/inmunologíaRESUMEN
Over the past decade, chimeric antigen receptor T cells have emerged as a breakthrough cancer therapy in selected hematologic malignancies. Translating the success of this therapy to solid tumors is challenging. In this issue, we discuss strategies potentially useful to increase the chimeric antigen receptor T-cell efficacy in this clinical indication. See related article by Fischer-Riepe et al., p. 3564.
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Inmunoterapia Adoptiva , Neoplasias , Receptores Quiméricos de Antígenos , Linfocitos T , Humanos , Receptores Quiméricos de Antígenos/inmunología , Inmunoterapia Adoptiva/métodos , Linfocitos T/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Gangliósidos/inmunología , Antígenos de Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/inmunologíaRESUMEN
Anti-ganglioside antibodies (anti-Gg Abs) have been linked to delayed/poor clinical recovery in both axonal and demyelinating forms of Guillain-Barrè Syndrome (GBS). In many instances, the incomplete recovery is attributed to the peripheral nervous system's failure to regenerate. The cross-linking of cell surface gangliosides by anti-Gg Abs triggers inhibition of nerve repair in both in vitro and in vivo axon regeneration paradigms. This mechanism involves the activation of the small GTPase RhoA, which negatively modulates the growth cone cytoskeleton. At present, the identity/es of the receptor/s responsible for transducing the signal that ultimately leads to RhoA activation remains poorly understood. The aim of this work was to identify the transducer molecule responsible for the inhibitory effect of anti-Gg Abs on nerve repair. Putative candidate molecules were identified through proteomic mass spectrometry of ganglioside affinity-captured proteins from rat cerebellar granule neurons (Prendergast et al., 2014). These candidates were evaluated using an in vitro model of neurite outgrowth with primary cultured dorsal root ganglion neurons (DRGn) and an in vivo model of axon regeneration. Using an shRNA-strategy to silence putative candidates on DRGn, we identified tumor necrosis factor receptor 1A protein (TNFR1A) as a transducer molecule for the inhibitory effect on neurite outgrowth from rat/mouse DRGn cultures of a well characterized mAb targeting the related gangliosides GD1a and GT1b. Interestingly, lack of TNFr1A expression on DRGn abolished the inhibitory effect on neurite outgrowth caused by anti-GD1a but not anti-GT1b specific mAbs, suggesting specificity of GD1a/transducer signaling. Similar results were obtained using primary DRGn cultures from TNFR1a-null mice, which did not activate RhoA after exposure to anti-GD1a mAbs. Generation of single point mutants at the stalk region of TNFR1A identified a critical amino acid for transducing GD1a signaling, suggesting a direct interaction. Finally, passive immunization with an anti-GD1a/GT1b mAb in an in vivo model of axon regeneration exhibited reduced inhibitory activity in TNFR1a-null mice compared to wild type mice. In conclusion, these findings identify TNFR1A as a novel transducer receptor for the inhibitory effect exerted by anti-GD1a Abs on nerve repair, representing a significant step forward toward understanding the factors contributing to poor clinical recovery in GBS associated with anti-Gg Abs.
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Axones , Gangliósidos , Inmunoglobulina G , Regeneración Nerviosa , Receptores Tipo I de Factores de Necrosis Tumoral , Proteína de Unión al GTP rhoA , Animales , Ratones , Ratas , Axones/metabolismo , Axones/inmunología , Células Cultivadas , Gangliósidos/metabolismo , Gangliósidos/inmunología , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/metabolismo , Síndrome de Guillain-Barré/patología , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Inmunoglobulina G/farmacología , Ratones Noqueados , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Proteína de Unión al GTP rhoA/metabolismo , Proteína de Unión al GTP rhoA/inmunología , Transducción de SeñalRESUMEN
Gangliosides represent glycolipids containing sialic acid residues, present on the cell membrane with glycan residues exposed to the extracellular matrix (ECM), while the ceramides are anchored within the membrane. These molecules play a critical role in pathophysiological processes such as host-pathogen interactions, cell-cell recognition, signal transduction, cell adhesion, motility, and immunomodulation. Accumulated evidence suggests the overexpression of gangliosides on tumor tissues in comparison to healthy human tissues. These tumor-associated gangliosides have been implicated in various facets of tumor biology, including cell motility, differentiation, signaling, immunosuppression, angiogenesis, and metastasis. Consequently, these entities emerge as attractive targets for immunotherapeutic interventions. Notably, the administration of antibodies targeting gangliosides has demonstrated cytotoxic effects on cancer cells that exhibit an overexpression of these glycolipids. Passive immunotherapy approaches utilizing murine or murine/human chimeric anti-ganglioside antibodies have been explored as potential treatments for diverse cancer types. Additionally, vaccination strategies employing tumor-associated gangliosides in conjunction with adjuvants have entered the realm of promising techniques currently undergoing clinical trials. The present comprehensive review encapsulates the multifaceted roles of gangliosides in tumor initiation, progression, immunosuppression, and metastasis. Further, an overview is provided of the correlation between the expression status of gangliosides in normal and tumor cells and its impact on cancer patient survival. Furthermore, the discussion extends to ongoing and completed clinical trials employing diverse strategies to target gangliosides, elucidating their effectiveness in treating cancers. This emerging discipline is expected to supply substantial impetus for the establishment of novel therapeutic strategies.
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Gangliósidos , Inmunomodulación , Inmunoterapia , Neoplasias , Humanos , Gangliósidos/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Animales , Inmunoterapia/métodosRESUMEN
Tetanus disease, caused by C. tetani, starts with wounds or mucous layer contact. Prevented by vaccination, the lack of booster shots throughout life requires prophylactic treatment in case of accidents. The incidence of tetanus is high in underdeveloped countries, requiring the administration of antitetanus antibodies, usually derived from immunized horses or humans. Heterologous sera represent risks such as serum sickness. Human sera can carry unknown viruses. In the search for human monoclonal antibodies (mAbs) against TeNT (Tetanus Neurotoxin), we previously identified a panel of mAbs derived from B-cell sorting, selecting two nonrelated ones that binded to the C-terminal domain of TeNT (HCR/T), inhibiting its interaction with the cellular receptor ganglioside GT1b. Here, we present the results of cellular assays and molecular docking tools. TeNT internalization in neurons is prevented by more than 50% in neonatal rat spinal cord cells, determined by quantitative analysis of immunofluorescence punctate staining of Alexa Fluor 647 conjugated to TeNT. We also confirmed the mediator role of the Synaptic Vesicle Glycoprotein II (SV2) in TeNT endocytosis. The molecular docking assays to predict potential TeNT epitopes showed the binding of both antibodies to the HCR/T domain. A higher incidence was found between N1153 and W1297 when evaluating candidate residues for conformational epitope.
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Anticuerpos Monoclonales , Endocitosis , Simulación del Acoplamiento Molecular , Neuronas , Toxina Tetánica , Animales , Ratas , Neuronas/metabolismo , Humanos , Anticuerpos Monoclonales/inmunología , Toxina Tetánica/inmunología , Toxina Tetánica/metabolismo , Tétanos/prevención & control , Tétanos/inmunología , Epítopos/inmunología , Gangliósidos/inmunología , Gangliósidos/metabolismo , Células Cultivadas , Simulación por Computador , MetaloendopeptidasasRESUMEN
BACKGROUND: Acute bulbar palsy-plus (ABPp) syndrome is an unusual variant of Guillain-Barré syndrome (GBS). Anti-GT1a and anti-GQ1b antibodies have been reported in patients with ABPp, but without reports related to GD3 antibodies. METHODS: Clinical data of a patient diagnosed as ABPp syndrome were reviewed clinically. And we summarized the GBS patients with ABP and facial paralysis reported in the literature. RESULTS: We reported a 13-year-old girl presented with asymmetric bifacial weakness, bulbar palsy and transient limb numbness, and had positive serum IgG anti-GD3 antibody. Through reviewing the GBS patients with ABP and facial paralysis reported previously, we found that facial palsy could be unilateral or bilateral. The bilateral facial palsy could present successively or simultaneously, and could be symmetrical or asymmetrical. Other common symptoms included ophthalmoplegia, sensory abnormality and ataxia. IgG anti-GT1a and IgG anti-GQ1b antibodies were the most frequent. Most of the patients had full recovery within two weeks to one year of follow-up. CONCLUSIONS: We reported a patient with asymmetric bifacial palsy and bulbar palsy, which seemed to fit the diagnosis of ABPp syndrome. This was the first report of ABPp variant of GBS with positive serum ganglioside GD3 IgG antibody.
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Gangliósidos , Síndrome de Guillain-Barré , Inmunoglobulina G , Humanos , Femenino , Gangliósidos/inmunología , Adolescente , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Autoanticuerpos/sangreRESUMEN
Introduction: The effector function of T cells is regulated via immune checkpoints, activating or inhibiting the immune response. The BTLA-HVEM complex, the inhibitory immune checkpoint, may act as one of the tumor immune escape mechanisms. Therefore, interfering with the binding of these proteins can prove beneficial in cancer treatment. Our study focused on peptides interacting with HVEM at the same place as BTLA, thus disrupting the BTLA-HVEM interaction. These peptides' structure and amino acid sequences are based on the gD protein, the ligand of HVEM. Here, we investigated their immunomodulatory potential in melanoma patients. Methods: Flow cytometry analyses of activation, proliferation, and apoptosis of T cells from patients were performed. Additionally, we evaluated changes within the T cell memory compartment. Results: The most promising compound - Pep(2), increased the percentages of activated T cells and promoted their proliferation. Additionally, this peptide affected the proliferation rate and apoptosis of melanoma cell line in co-culture with T cells. Discussion: We conclude that the examined peptide may act as a booster for the immune system. Moreover, the adjuvant and activating properties of the gD-derived peptide could be used in a combinatory therapy with currently used ICI-based treatment. Our studies also demonstrate that even slight differences in the amino acid sequence of peptides and any changes in the position of the disulfide bond can strongly affect the immunomodulatory properties of compounds.
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Activación de Linfocitos , Melanoma , Receptores Inmunológicos , Miembro 14 de Receptores del Factor de Necrosis Tumoral , Linfocitos T , Humanos , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Miembro 14 de Receptores del Factor de Necrosis Tumoral/metabolismo , Miembro 14 de Receptores del Factor de Necrosis Tumoral/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Activación de Linfocitos/efectos de los fármacos , Femenino , Masculino , Persona de Mediana Edad , Proliferación Celular/efectos de los fármacos , Anciano , Línea Celular Tumoral , Adulto , Apoptosis/efectos de los fármacos , Péptidos/farmacología , Péptidos/inmunología , Gangliósidos/inmunologíaRESUMEN
Bilateral facial palsy with paresthesia (FDP) is a rare variant of GBS, characterized by simultaneous bilateral facial palsy and paresthesia of the distal limbs. Mounting evidence indicates that the presence of anti-GT1a IgG has a pathogenic role as an effector molecule in the development of cranial nerve palsies in certain patients with GBS, whereas anti-GT1a antibody is rarely presented positive in FDP. Here, we report the case of a 33-year-old male diagnosed with FDP presented with acute onset of bilateral facial palsy and slight paresthesias at the feet as the only neurological manifestation. An antecedent infection with no identifiable reason for the fever or skin eruptions was noted in the patient. He also exhibited cerebrospinal fluid albuminocytologic dissociation and abnormal nerve conduction studies. Notably, the testing of specific serum anti-gangliosides showed positive anti-GT1a IgG/IgM Ab. The patient responded well to intravenous immunoglobulin therapy. This case brings awareness to a rare variant of GBS, and provides the first indication that anti-GT1a antibodies play a causative role in the development of FDP. The case also suggests that prompt management with IVIG should be implemented if FDP is diagnosed.
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Autoanticuerpos , Parálisis Facial , Gangliósidos , Parestesia , Humanos , Masculino , Adulto , Parestesia/inmunología , Parestesia/diagnóstico , Parestesia/etiología , Parálisis Facial/diagnóstico , Parálisis Facial/etiología , Parálisis Facial/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Gangliósidos/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/inmunologíaRESUMEN
PURPOSE: T cells modified with chimeric antigen receptors (CARTs) have demonstrated efficacy for hematologic malignancies; however, benefit for patients with CNS tumors has been limited. To enhance T cell activity against GD2+ CNS malignancies, we modified GD2-directed CART cells (GD2.CARTs) with a constitutively active interleukin (IL)-7 receptor (C7R-GD2.CARTs). METHODS: Patients age 1-21 years with H3K27-altered diffuse midline glioma (DMG) or other recurrent GD2-expressing CNS tumors were eligible for this phase I trial (ClinicalTrials.gov identifier: NCT04099797). All subjects received standard-of-care adjuvant radiation therapy or chemotherapy before study enrollment. The first treatment cohort received GD2.CARTs alone (1 × 107 cells/m2), and subsequent cohorts received C7R-GD2.CARTs at two dose levels (1 × 107 cells/m2; 3 × 107 cells/m2). Standard lymphodepletion with cyclophosphamide and fludarabine was included at all dose levels. RESULTS: Eleven patients (age 4-18 years) received therapy without dose-limiting toxicity. The GD2.CART cohort did not experience toxicity, but had disease progression after brief improvement of residual neurologic deficits (≤3 weeks). The C7R-GD2.CART cohort developed grade 1 tumor inflammation-associated neurotoxicity in seven of eight (88%) cases, controllable with anakinra. Cytokine release syndrome was observed in six of eight (75%, grade 1 in all but one patient) and associated with increased circulating IL-6 and IP-10 (P < .05). Patients receiving C7R-GD2.CARTs experienced temporary improvement from baseline neurologic deficits (range, 2 to >12 months), and seven of eight (88%) remained eligible for additional treatment cycles (range 2-4 cycles). Partial responses by iRANO criteria were observed in two of seven (29%) patients with DMG treated by C7R-GD2.CARTs. CONCLUSION: Intravenous GD2.CARTs with and without C7R were well tolerated. Patients treated with C7R-GD2.CARTs exhibited transient improvement of neurologic deficits and increased circulating cytokines/chemokines. Treatment with C7R-GD2.CARTs represents a novel approach warranting further investigation for children with these incurable CNS cancers.
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Neoplasias del Sistema Nervioso Central , Gangliósidos , Receptores Quiméricos de Antígenos , Humanos , Niño , Adolescente , Preescolar , Masculino , Femenino , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéutico , Lactante , Adulto Joven , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/inmunología , Neoplasias del Sistema Nervioso Central/terapia , Gangliósidos/inmunología , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Clasificación del Tumor , Glioma/tratamiento farmacológico , Glioma/patología , Glioma/terapia , Glioma/inmunología , Subunidad alfa del Receptor de Interleucina-7RESUMEN
Fisher syndrome is recognized as a variant of Guillain-Barré syndrome, encompassing acute onset immune-mediated neuropathies marked by the classical triad of ataxia, areflexia, and ophthalmoplegia. Generally, Fisher syndrome follows a self-limited course with a good prognosis. Ophthalmoplegia, typically bilateral, progresses to complete external ophthalmoplegia within 1-2 weeks. Ataxia, often very severe, may cause an inability to walk without support despite normal strength. Fisher syndrome is also frequently concomitant with additional clinical features, including ptosis, internal ophthalmoplegia, facial nerve palsy, sensory deficits, and bulbar palsy. The confirmation of an antecedent infection is often established. Among the ganglioside antibodies, anti-GQ1b antibodies exhibit positivity in over 80% of patients. The syndrome manifests in three distinct types: a partial subtype exhibiting only a subset of the triad symptoms, Bickerstaff's brainstem encephalitis marked by impaired consciousness and pyramidal tract signs, and an overlapping subtype with Guillain-Barré syndrome, characterized by weakness in the extremities.
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Síndrome de Miller Fisher , Humanos , Síndrome de Miller Fisher/diagnóstico , Síndrome de Miller Fisher/inmunología , Síndrome de Miller Fisher/terapia , Síndrome de Miller Fisher/fisiopatología , Gangliósidos/inmunología , Pronóstico , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/terapiaRESUMEN
Background: Neuroblastoma (NB) is characterized by both adrenergic (ADRN) and undifferentiated mesenchymal (MES) subsets. The ganglioside sialic acid-containing glycosphingolipid (GD2) is widely overexpressed on tumors of neuroectodermal origin promoting malignant phenotypes. MES cells are greatly enriched in post-therapy and relapsing tumors and are characterized by decreased expression of GD2. This event may cause failure of GD2-based immunotherapy. NK cells represent a key innate cell subset able to efficiently kill tumors. However, the tumor microenvironment (TME) that includes tumor cells and tumor-associated (TA) cells could inhibit their effector function. Methods: We studied eight NB primary cultures that, in comparison with commercial cell lines, more faithfully reflect the tumor cell characteristics. We studied four primary NB-MES cell cultures and two pairs of MES/ADRN (691 and 717) primary cultures, derived from the same patient. In particular, in the six human NB primary cultures, we assessed their phenotype, the expression of GD2, and the enzymes that control its expression, as well as their interactions with NK cells, using flow cytometry, RT-qPCR, and cytotoxicity assays. Results: We identified mature (CD105+/CD133-) and undifferentiated (CD133+/CD105-) NB subsets that express high levels of the MES transcripts WWTR1 and SIX4. In addition, undifferentiated MES cells display a strong resistance to NK-mediated killing. On the contrary, mature NB-MES cells display an intermediate resistance to NK-mediated killing and exhibit some immunomodulatory capacities on NK cells but do not inhibit their cytolytic activity. Notably, independent from their undifferentiated or mature phenotype, NB-MES cells express GD2 that can be further upregulated in undifferentiated NB-MES cells upon co-culture with NK cells, leading to the generation of mature mesenchymal GD2bright neuroblasts. Concerning 691 and 717, they show high levels of GD2 and resistance to NK cell-mediated killing that can be overcome by the administration of dinutuximab beta, the anti-GD2 monoclonal antibody applied in the clinic. Conclusions: NB is a heterogeneous tumor representing a further hurdle in NB immunotherapy. However, different from what was reported with NB commercial cells and independent of their MES/ADRN phenotype, the expression of GD2 and its displayed sensitivity to anti-GD2 mAb ADCC indicated the possible effectiveness of anti-GD2 immunotherapy.
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Gangliósidos , Células Asesinas Naturales , Neuroblastoma , Humanos , Línea Celular Tumoral , Citotoxicidad Inmunológica , Gangliósidos/inmunología , Gangliósidos/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Neuroblastoma/inmunología , Neuroblastoma/metabolismo , Células Tumorales Cultivadas , Escape del Tumor , Microambiente Tumoral/inmunologíaRESUMEN
Importance: The discovery of the anti-GQ1b antibody has expanded the nosology of classic Miller Fisher syndrome to include Bickerstaff brainstem encephalitis, Guillain-Barré syndrome with ophthalmoplegia, and acute ophthalmoplegia without ataxia, which have been brought under the umbrella term anti-GQ1b antibody syndrome. It seems timely to define the phenotypes of anti-GQ1b antibody syndrome for the proper diagnosis of this syndrome with diverse clinical presentations. This review summarizes these syndromes and introduces recently identified subtypes. Observations: Although ophthalmoplegia is a hallmark of anti-GQ1b antibody syndrome, recent studies have identified this antibody in patients with acute vestibular syndrome, optic neuropathy with disc swelling, and acute sensory ataxic neuropathy of atypical presentation. Ophthalmoplegia associated with anti-GQ1b antibody positivity is complete in more than half of the patients but may be monocular or comitant. The prognosis is mostly favorable; however, approximately 14% of patients experience relapse. Conclusions and Relevance: Anti-GQ1b antibody syndrome may present diverse neurological manifestations, including ophthalmoplegia, ataxia, areflexia, central or peripheral vestibulopathy, and optic neuropathy. Understanding the wide clinical spectrum may aid in the differentiation and management of immune-mediated neuropathies with multiple presentations.
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Autoanticuerpos , Gangliósidos , Síndrome de Miller Fisher , Oftalmoplejía , Humanos , Gangliósidos/inmunología , Oftalmoplejía/inmunología , Oftalmoplejía/diagnóstico , Síndrome de Miller Fisher/inmunología , Síndrome de Miller Fisher/diagnóstico , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/diagnósticoRESUMEN
BACKGROUND: There have been multiple reports about the occurrence of dysphagia after the contraction of coronavirus disease 2019 (COVID-19). However, a detailed pathology and epidemiologic relation between COVID-19 infection and dysphagia have yet to be established. Here, we report three cases of unexplained dysphagia after COVID-19 diagnosis, with atypical clinical presentations. CASE REPORT: All patients showed severe isolated lower cranial nerve involvement with dysphagia and aspiration, which required full tube feeding but showed no evidence of limb weakness or sensory symptoms. All tested positive for anti-ganglioside antibody tests, which all commonly (GD1b, GM1, and GQ1b) are known to have terminal NeuNAc(α2-3)Gal epitope. DISCUSSION: We report a series of cases featuring severe, isolated dysphagia post-COVID-19 infection, concomitant with positive anti-ganglioside antibodies. One potential etiology is a variant of Guillain-Barré syndrome. Because only isolated dysphagia with sparing of the facial and extraocular muscles was evident in these cases, we explore the association between anti-ganglioside antibodies specific to NeuNAc(α2-3)Gal, which has been frequently associated with the development of bulbar dysfunction. Given that NeuNAc(α2-3)Gal exhibits an affinity for the spike glycoprotein of SARS-CoV-2, a cross-reaction against NeuNAc(α2-3)Gal may possibly contribute to isolated dysphagia following COVID-19 infection.
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COVID-19 , Trastornos de Deglución , Gangliósidos , Anciano , Femenino , Humanos , Masculino , Autoanticuerpos/sangre , COVID-19/complicaciones , COVID-19/inmunología , Trastornos de Deglución/etiología , Gangliósidos/inmunología , Síndrome de Guillain-Barré/inmunología , SARS-CoV-2/inmunología , Anciano de 80 o más AñosRESUMEN
Aberrant glycosylation is a key mechanism employed by cancer cells to evade immune surveillance, induce angiogenesis and metastasis, among other hallmarks of cancer. Sialic acids, distinctive terminal glycan structures located on glycoproteins or glycolipids, are prominently upregulated across various tumor types, including colorectal cancer (CRC). Sialylated glycans modulate anti-tumor immune responses through their interactions with Siglecs, a family of glycan-binding receptors with specificity for sialic acid-containing glycoconjugates, often resulting in immunosuppression. In this paper, we investigated the immunomodulatory function of ST3Gal5, a sialyltransferase that catalyzes the addition of α2-3 sialic acids to glycosphingolipids, since lower expression of ST3Gal5 is associated with better survival of CRC patients. We employed CRISPR/Cas9 to knock out the ST3Gal5 gene in two murine CRC cell lines MC38 and CT26. Glycomics analysis confirmed the removal of sialic acids on glycolipids, with no discernible impact on glycoprotein sialylation. Although knocking out ST3Gal5 in both cell lines did not affect in vivo tumor growth, we observed enhanced levels of regulatory T cells in CT26 tumors lacking ST3Gal5. Moreover, we demonstrate that the absence of ST3Gal5 affected size and blood vessel density only in MC38 tumors. In summary, we ascertain that sialylation of glycosphingolipids has a limited influence on the anti-tumor immune response in CRC, despite detecting alterations in the tumor microenvironment, possibly due to a shift in ganglioside abundance.
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Neoplasias Colorrectales , Gangliósidos , Sialiltransferasas , Sialiltransferasas/metabolismo , Sialiltransferasas/genética , Gangliósidos/metabolismo , Gangliósidos/inmunología , Animales , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Ratones , Línea Celular Tumoral , Humanos , beta-Galactosida alfa-2,3-SialiltransferasaRESUMEN
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions. METHODS: We conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients. In this study, the GD2-CAR-T therapy was evaluated for the first time in metastatic melanoma patients in combination with BRAF/MEK inhibitor therapy, and as a monotherapy in patients with colorectal cancer and a patient with fibromyxoid sarcoma. Feasibility and safety were determined and persistence studies, multiplex cytokine arrays on sera and detailed immune phenotyping of the original CAR-T products, the circulating CAR-T cells, and, in select patients, the tumor-infiltrating CAR-T cells were performed. RESULTS: We demonstrate the feasibility of manufacturing CAR-T products at point of care for patients with solid cancer and show that a single intravenous infusion was well tolerated with no dose-limiting toxicities or severe adverse events. In addition, we note significant improvements in CAR-T cell immune phenotype, and expansion when a modified manufacturing procedure was adopted for the latter 6 patients recruited to this 12-patient trial. We also show evidence of CAR-T cell-mediated immune activity and in some patients expanded subsets of circulating myeloid cells after CAR-T cell therapy. CONCLUSIONS: This is the first report of third-generation GD2-targeting CAR-T cells in patients with metastatic melanoma and other solid cancers such as colorectal cancer, showing feasibility, safety and immune activity, but limited clinical effect. TRIAL REGISTRATION NUMBER: ACTRN12613000198729.
Asunto(s)
Inmunoterapia Adoptiva , Melanoma , Receptores Quiméricos de Antígenos , Humanos , Melanoma/inmunología , Melanoma/terapia , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Receptores Quiméricos de Antígenos/inmunología , Masculino , Femenino , Persona de Mediana Edad , Gangliósidos/inmunología , Adulto , Anciano , Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND & PURPOSE: In this retrospective study, we aimed at defining the clinical, paraclinical and outcome features of acute neurological syndromes associated with anti-GQ1b antibodies. RESULTS: We identified 166 patients with neurological symptoms appearing in less than 1 month and anti-GQ1b antibodies in serum between 2012 and 2022. Half were female (51%), mean age was 50 years (4-90), and the most frequent clinical features were areflexia (80% of patients), distal upper and lower limbs sensory symptoms (78%), ophthalmoplegia (68%), sensory ataxia (67%), limb muscle weakness (45%) and bulbar weakness (45%). Fifty-three patients (32%) presented with complete (21%) and incomplete (11%) Miller Fisher syndrome (MFS), thirty-six (22%) with Guillain-Barre syndrome (GBS), one (0.6%) with Bickerstaff encephalitis (BE), and seventy-three (44%) with mixed MFS, GBS & BE clinical features. Nerve conduction studies were normal in 46% of cases, showed demyelination in 28%, and axonal loss in 23%. Anti-GT1a antibodies were found in 56% of cases, increased cerebrospinal fluid protein content in 24%, and Campylobacter jejuni infection in 7%. Most patients (83%) were treated with intravenous immunoglobulins, and neurological recovery was complete in 69% of cases at 1 year follow-up. One patient died, and 15% of patients relapsed. Age > 70 years, initial Intensive Care Unit (ICU) admission, and absent anti-GQ1b IgG antibodies were predictors of incomplete recovery at 12 months. No predictors of relapse were identified. CONCLUSION: This study from Western Europe shows acute anti-GQ1b antibody syndrome presents with a large clinical phenotype, a good outcome in 2/3 of cases, and frequent relapses.
Asunto(s)
Autoanticuerpos , Gangliósidos , Síndrome de Miller Fisher , Humanos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Gangliósidos/inmunología , Anciano , Estudios Retrospectivos , Adulto Joven , Adolescente , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Anciano de 80 o más Años , Síndrome de Miller Fisher/fisiopatología , Síndrome de Miller Fisher/sangre , Síndrome de Miller Fisher/diagnóstico , Niño , Preescolar , Síndrome de Guillain-Barré/sangre , Síndrome de Guillain-Barré/fisiopatología , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/inmunologíaRESUMEN
PURPOSE: Cytokine-engineering of chimeric antigen receptor-redirected T cells (CAR T cells) is a promising principle to overcome the limited activity of canonical CAR T cells against solid cancers. EXPERIMENTAL DESIGN: We developed an investigational medicinal product, GD2IL18CART, consisting of CAR T cells directed against ganglioside GD2 with CAR-inducible IL18 to enhance their activation response and cytolytic effector functions in the tumor microenvironment. To allow stratification of patients according to tumor GD2 expression, we established and validated immunofluorescence detection of GD2 on paraffin-embedded tumor tissues. RESULTS: Lentiviral all-in-one vector engineering of human T cells with the GD2-specific CAR with and without inducible IL18 resulted in cell products with comparable proportions of CAR-expressing central memory T cells. Production of IL18 strictly depends on GD2 antigen engagement. GD2IL18CART respond to interaction with GD2-positive tumor cells with higher IFNγ and TNFα cytokine release and more effective target cytolysis compared with CAR T cells without inducible IL18. GD2IL18CART further have superior in vivo antitumor activity, with eradication of GD2-positive tumor xenografts. Finally, we established GMP-compliant manufacturing of GD2IL18CART and found it to be feasible and efficient at clinical scale. CONCLUSIONS: These results pave the way for clinical investigation of GD2IL18CART in pediatric and adult patients with neuroblastoma and other GD2-positive cancers (EU CT 2022- 501725-21-00). See related commentary by Locatelli and Quintarelli, p. 3361.
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Gangliósidos , Inmunoterapia Adoptiva , Interleucina-18 , Neoplasias , Receptores Quiméricos de Antígenos , Linfocitos T , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Gangliósidos/inmunología , Interleucina-18/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Ratones , Inmunoterapia Adoptiva/métodos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/patología , Línea Celular Tumoral , Microambiente Tumoral/inmunología , FemeninoRESUMEN
BACKGROUND AND PURPOSE: Takotsubo cardiomyopathy (TCM) is a serious autonomic complication of Guillain-Barré syndrome (GBS). However, the association between TCM and GBS has not been investigated in detail. We investigated the characteristics of GBS patients with TCM (GBS-TCM). METHODS: Clinical features and anti-ganglioside antibody between the GBS-TCM patients and 62 classical GBS patients without TCM as control patients were compared. RESULTS: Eight GBS-TCM patients were identified, in whom TCM was diagnosed at a mean of 6.5 [range 3-42] days after the onset of GBS. The age at onset of GBS was elder in the GBS-TCM patients than in the control GBS patients (76.5 [56-87] vs. 52 [20-88] years, p < 0.01). Notably, cranial nerve deficits, particularly in the lower cranial nerves, were observed in all GBS-TCM patients (100% vs. 41.9%, p < 0.01). Additionally, the GBS-TCM patients showed a higher GBS disability score at nadir (5 [4-5] vs. 4 [1-5], p < 0.01), and lower Medical Research Council sum scores at admission and nadir (37 [30-44] vs. 48 [12-60] at admission, p < 0.05, and 20 [12-44] vs. 40 [0-60] at nadir, p < 0.05, respectively). Mechanical ventilation was more frequently required in the GBS-TCM patients (62.5% vs. 11.3%, p < 0.01). Three GBS-TCM patients were positive for anti-ganglioside antibodies. CONCLUSIONS: TCM occurred at a relatively early phase of GBS. The characteristics of GBS-TCM were the elder, lower cranial nerve involvements, severe limb weakness, and respiratory failure.
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Síndrome de Guillain-Barré , Cardiomiopatía de Takotsubo , Humanos , Cardiomiopatía de Takotsubo/etiología , Cardiomiopatía de Takotsubo/complicaciones , Síndrome de Guillain-Barré/complicaciones , Síndrome de Guillain-Barré/fisiopatología , Femenino , Persona de Mediana Edad , Anciano , Masculino , Anciano de 80 o más Años , Adulto , Adulto Joven , Gangliósidos/inmunología , Autoanticuerpos/sangre , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: Antiganglioside antibodies (AGAs) might be involved in the etiopathogenesis of many neurological diseases, such as Miller-Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS). Available comprehensive reference data regarding AGA positivity rates and cross-responsiveness among AGAs (where one line immunoblot is positive for ≥1 AGA) during routine clinical care are scant. METHODS: In this 10-year monocentric retrospective study, 3560 immunoglobulin (Ig) G and IgM line blots (GA Generic Assays' Anti-Ganglioside Dot kit) obtained using cerebrospinal fluid (CSF) and serum samples from 1342 patients were analyzed for AGA positivity in terms of 14 diagnosis categories and AGA cross-responsiveness. RESULTS: Of all 3560 line blots 158 (4.4%) and of all CSF samples 0.4% (4/924) CSF line blots were AGA positive. For serum IgG, blots with positivity rates higher than the standard deviation of 15.6% were associated with MFS (GD3, GD1a, GT1a and GQ1b) and acute motor axonal neuropathy (AMAN) (GM1, GD1a and GT1a). For serum IgM, blots with positivity rates higher than the standard deviation of 8.1% were associated with AMAN (GM2, GT1a and GQ1b), MFS (GM1, GT1a and GQ1b), multifocal motor neuropathy (MMN) (GM1, GM2 and GQ1b) and chronic inflammatory demyelinating polyneuropathy (CIDP) (GM1). Cross-responsiveness was observed in 39.6% of all positive serum AGA. CONCLUSIONS: Testing for AGAs during routine clinical care rarely led to positive findings, both in serum and even less in CSF, except for the diagnoses AMAN, MFS, MMN and CIDP. Nonspecific findings found as cross-responsiveness between different AGA samples occur frequently, impacting the positivity of most AGA subtypes.