RESUMO
Pediatric brain tumors are the primary cause of death in children with cancer. Diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG) are frequently unresectable due to their difficult access location, and 5-year survival remains less than 20%. Despite significant advances in tumor biology and genetics, treatment options remain limited and ineffective. Immunotherapy using T cells with a chimeric antigen receptor (CAR) that has been genetically engineered is quickly emerging as a new treatment option for these patients. High levels of expression were detected for both disialoganglioside (GD2) and B7-H3 in pediatric DMG/DIPG. Numerous studies have been conducted in recent years employing various generations of GD2-CAR T cells. The two most prevalent adverse effects found with this therapy are cytokine release syndrome, which varies in severity from mild constitutional symptoms to a high-grade disease associated with potentially fatal multi-organ failure, and neurotoxicity, known as CAR T-cell-related encephalopathy syndrome. During the acute phase of anticancer action, peri-tumoral neuro-inflammation might cause deadly hydrocephalus. The initial results of clinical trials show that the outcomes are not highly encouraging as B cell malignancies and myelomas. In vivo research on CAR T-cell therapy for DIPG has yielded encouraging results, but in human trials, the early results have shown potentially fatal side effects and very modest, but fleeting improvements. Solid tumors present a hindrance to CAR T-cell therapy because of the antigenic dilemma and the strong immune-suppressing tumor microenvironment.
Assuntos
Glioma , Imunoterapia Adotiva , Humanos , Glioma/terapia , Glioma/imunologia , Criança , Imunoterapia Adotiva/métodos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Neoplasias do Tronco Encefálico/terapia , Neoplasias do Tronco Encefálico/imunologiaRESUMO
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM) are two highly aggressive and generally incurable gliomas with little therapeutic advancements made in the past several decades. Despite immense initial success of chimeric antigen receptor (CAR) T cells for the treatment of leukemia and lymphoma, significant headway into the application of CAR-T cells against solid tumors, including gliomas, is still forthcoming. The integrin complex alphav beta3 (αvß3) is present on multiple and diverse solid tumor types and tumor vasculature with limited expression throughout most normal tissues, qualifying it as an appealing target for CAR-T cell-mediated immunotherapy. METHODS: Patient-derived DIPG and GBM cell lines were evaluated by flow cytometry for surface expression of αvß3. Second-generation CAR-T cells expressing an anti-αvß3 single-chain variable fragment were generated by retroviral transduction containing either a CD28 or 4-1BB costimulatory domain and CD3zeta. CAR-T cells were evaluated by flow cytometry for CAR expression, memory phenotype distribution, and inhibitory receptor profile. DIPG and GBM cell lines were orthotopically implanted into NSG mice via stereotactic injection and monitored with bioluminescent imaging to evaluate αvß3 CAR-T cell-mediated antitumor responses. RESULTS: We found that patient-derived DIPG cells and GBM cell lines express high levels of surface αvß3 by flow cytometry, while αvß3 is minimally expressed on normal tissues by RNA sequencing and protein microarray. The manufactured CAR-T cells consisted of a substantial frequency of favorable early memory cells and a low inhibitory receptor profile. αvß3 CAR-T cells demonstrated efficient, antigen-specific tumor cell killing in both cytotoxicity assays and in in vivo models of orthotopically and stereotactically implanted DIPG and GBM tumors into relevant locations in the brain of NSG mice. Tumor responses were rapid and robust with systemic CAR-T cell proliferation and long-lived persistence associated with long-term survival. Following tumor clearance, TCF-1+αvß3 CAR-T cells were detectable, underscoring their ability to persist and undergo self-renewal. CONCLUSIONS: These results highlight the potential of αvß3 CAR-T cells for immunotherapeutic treatment of aggressive brain tumors with reduced risk of on-target, off-tumor mediated toxicity due to the restricted nature of αvß3 expression in normal tissues.
Assuntos
Neoplasias do Tronco Encefálico/imunologia , Glioma Pontino Intrínseco Difuso/imunologia , Glioblastoma/imunologia , Integrina beta3/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Animais , Modelos Animais de Doenças , Glioblastoma/patologia , Humanos , CamundongosRESUMO
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.
Assuntos
Astrocitoma , Neoplasias do Tronco Encefálico , Gangliosídeos , Glioma , Histonas , Imunoterapia Adotiva , Mutação , Receptores de Antígenos Quiméricos , Astrocitoma/genética , Astrocitoma/imunologia , Astrocitoma/patologia , Astrocitoma/terapia , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Criança , Gangliosídeos/imunologia , Perfilação da Expressão Gênica , Glioma/genética , Glioma/imunologia , Glioma/patologia , Glioma/terapia , Histonas/genética , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/imunologia , Neoplasias da Medula Espinal/patologia , Neoplasias da Medula Espinal/terapiaRESUMO
Diffuse midline glioma (DMG) is an incurable malignancy with the highest mortality rate among pediatric brain tumors. While radiotherapy and chemotherapy are the most common treatments, these modalities have limited promise. Due to their diffuse nature in critical areas of the brain, the prognosis of DMG remains dismal. DMGs are characterized by unique phenotypic heterogeneity and histological features. Mutations of H3K27M, TP53, and ACVR1 drive DMG tumorigenesis. Histological artifacts include pseudopalisading necrosis and vascular endothelial proliferation. Mouse models that recapitulate human DMG have been used to study key driver mutations and the tumor microenvironment. DMG consists of a largely immunologically cold tumor microenvironment that lacks immune cell infiltration, immunosuppressive factors, and immune surveillance. While tumor-associated macrophages are the most abundant immune cell population, there is reduced T lymphocyte infiltration. Immunotherapies can stimulate the immune system to find, attack, and eliminate cancer cells. However, it is critical to understand the immune microenvironment of DMG before designing immunotherapies since differences in the microenvironment influence treatment efficacy. To this end, our review aims to overview the immune microenvironment of DMG, discuss emerging insights about the immune landscape that drives disease pathophysiology, and present recent findings and new opportunities for therapeutic discovery.
Assuntos
Neoplasias do Tronco Encefálico/imunologia , Glioma Pontino Intrínseco Difuso/imunologia , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Animais , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/terapia , HumanosRESUMO
BACKGROUNDPatients with diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+, H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine.METHODSNewly diagnosed patients, aged 3-21 years, with HLA-A*02.01+ and H3.3K27M+ status were enrolled in stratum A (DIPG) or stratum B (nonpontine DMG). Vaccine was administered in combination with polyinosinic-polycytidylic acid-poly-I-lysine carboxymethylcellulose (poly-ICLC) every 3 weeks for 8 cycles, followed by once every 6 weeks. Immunomonitoring and imaging were performed every 3 months. Imaging was centrally reviewed. Immunological responses were assessed in PBMCs using mass cytometry.RESULTSA total of 19 patients were enrolled in stratum A (median age,11 years) and 10 in stratum B (median age, 13 years). There were no grade-4 treatment-related adverse events (TRAEs). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22%-73%) for patients in stratum A and 39% (95% CI, 16%-93%) for patients in stratum B. The median OS was 16.1 months for patients who had an expansion of H3.3K27M-reactive CD8+ T cells compared with 9.8 months for their counterparts (P = 0.05). Patients with DIPG with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared with their counterparts (P < 0.01). Immediate pretreatment dexamethasone administration was inversely associated with H3.3K27M-reactive CD8+ T cell responses.CONCLUSIONAdministration of the H3.3K27M-specific vaccine was well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared with nonresponders.TRIAL REGISTRATIONClinicalTrials.gov NCT02960230.FUNDINGThe V Foundation, the Pacific Pediatric Neuro-Oncology Consortium Foundation, the Pediatric Brain Tumor Foundation, the Mithil Prasad Foundation, the MCJ Amelior Foundation, the Anne and Jason Farber Foundation, Will Power Research Fund Inc., the Isabella Kerr Molina Foundation, the Parker Institute for Cancer Immunotherapy, and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R35NS105068).
Assuntos
Neoplasias do Tronco Encefálico , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Citometria de Fluxo , Glioma , Histonas , Imunidade Celular/efeitos dos fármacos , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Adolescente , Adulto , Substituição de Aminoácidos , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/terapia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Criança , Pré-Escolar , Feminino , Glioma/genética , Glioma/imunologia , Glioma/terapia , Histonas/genética , Histonas/imunologia , Humanos , Imunidade Celular/genética , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologiaRESUMO
PURPOSE: Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, Activin A receptor type I (ACVR1)-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy. EXPERIMENTAL DESIGN: We utilized the Sleeping Beauty transposase system to generate an endogenous mouse model of mACVR1 brainstem glioma. Histology was used to characterize and validate the model. We performed RNA-sequencing analysis on neurospheres harboring mACVR1. mACVR1 neurospheres were implanted into the pons of immune-competent mice to test the therapeutic efficacy and toxicity of immune-stimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). mACVR1 neurospheres expressing the surrogate tumor antigen ovalbumin were generated to investigate whether TK/Flt3L treatment induces the recruitment of tumor antigen-specific T cells. RESULTS: Histologic analysis of mACVR1 tumors indicates that they are localized in the brainstem and have increased downstream signaling of bone morphogenetic pathway as demonstrated by increased phospho-smad1/5 and Id1 levels. Transcriptome analysis of mACVR1 neurosphere identified an increase in the TGFß signaling pathway and the regulation of cell differentiation. Adenoviral delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in antitumor immunity, recruitment of antitumor-specific T cells, and increased median survival (MS). CONCLUSIONS: This study provides insights into the phenotype and function of the tumor immune microenvironment in a mouse model of brainstem glioma harboring mACVR1. Immune-stimulatory gene therapy targeting the hosts' antitumor immune response inhibits tumor progression and increases MS of mice bearing mACVR1 tumors.
Assuntos
Neoplasias do Tronco Encefálico/terapia , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Glioma/terapia , Imunoterapia/métodos , Receptores de Ativinas Tipo I/genética , Animais , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/patologia , Modelos Animais de Doenças , Feminino , Vetores Genéticos/genética , Glioma/genética , Glioma/imunologia , Glioma/patologia , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Mutação , Ponte/patologia , Cultura Primária de Células , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Esferoides Celulares , Timidina Quinase/genética , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas/transplante , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
PURPOSE OF REVIEW: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem malignancy. Despite advances in understanding of the molecular underpinnings of the tumor in the past decade, the dismal prognosis of DIPG has thus far remained unchanged. This review seeks to highlight promising therapeutic targets within three arenas: DIPG cell-intrinsic vulnerabilities, immunotherapeutic approaches to tumor clearance, and microenvironmental dependencies that promote tumor growth. RECENT FINDINGS: Promising therapeutic strategies from recent studies include epigenetic modifying agents such as histone deacetylase inhibitors, bromodomain and extra-terminal motif (BET) protein inhibitors, and CDK7 inhibitors. Tumor-specific immunotherapies are emerging. Key interactions between DIPG and normal brain cells are coming to light, and targeting critical microenvironmental mechanisms driving DIPG growth in the developing childhood brain represents a new direction for therapy. SUMMARY: Several DIPG treatment strategies are being evaluated in early clinical trials. Ultimately, we suspect that a multifaceted therapeutic approach utilizing cell-intrinsic, microenvironmental, and immunotherapeutic targets will be necessary for eradicating DIPG.
Assuntos
Neoplasias do Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/terapia , Animais , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/imunologia , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/imunologia , Humanos , Terapia de Alvo MolecularRESUMO
BACKGROUND: Immunotherapy has shown remarkable clinical promise in the treatment of various types of cancers. However, clinical benefits derive from a highly inflammatory mechanism of action. This presents unique challenges for use in pediatric brainstem tumors including diffuse intrinsic pontine glioma (DIPG), since treatment-related inflammation could cause catastrophic toxicity. Therefore, the goal of this study was to investigate whether inflammatory, immune-based therapies are likely to be too dangerous to pursue for the treatment of pediatric brainstem tumors. METHODS: To complement previous immunotherapy studies using patient-derived xenografts in immunodeficient mice, we developed fully immunocompetent models of immunotherapy using transplantable, syngeneic tumors. These four models - HSVtk/GCV suicide gene immunotherapy, oncolytic viroimmunotherapy, adoptive T cell transfer, and CAR T cell therapy - have been optimized to treat tumors outside of the CNS and induce a broad spectrum of inflammatory profiles, maximizing the chances of observing brainstem toxicity. RESULTS: All four models achieved anti-tumor efficacy in the absence of toxicity, with the exception of recombinant vaccinia virus expressing GMCSF, which demonstrated inflammatory toxicity. Histology, imaging, and flow cytometry confirmed the presence of brainstem inflammation in all models. Where used, the addition of immune checkpoint blockade did not introduce toxicity. CONCLUSIONS: It remains imperative to regard the brainstem with caution for immunotherapeutic intervention. Nonetheless, we show that further careful development of immunotherapies for pediatric brainstem tumors is warranted to harness the potential potency of anti-tumor immune responses, despite their possible toxicity within this anatomically sensitive location.
Assuntos
Neoplasias do Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/terapia , Terapia Genética/métodos , Imunoterapia Adotiva/métodos , Terapia Viral Oncolítica/métodos , Linfócitos T/transplante , Animais , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/imunologia , Linhagem Celular Tumoral , Glioma Pontino Intrínseco Difuso/imunologia , Feminino , Genes Transgênicos Suicidas , Terapia Genética/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Camundongos , Terapia Viral Oncolítica/efeitos adversos , Resultado do Tratamento , Vaccinia virus/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal CNS tumor diagnosed in 300 American children per year. Radiation is the only effective treatment and extends overall survival to a median of 11 months. Due to its location in the brainstem, DIPG cannot be surgically resected. Immunotherapy has the ability to target tumor cells specifically; however, little is known about the tumor microenvironment in DIPGs. We sought to characterize infiltrating immune cells and immunosuppressive factor expression in pediatric low- and high-grade gliomas and DIPG. Methods: Tumor microarrays were stained for infiltrating immune cells. RNA was isolated from snap-frozen tumor tissue and Nanostring analysis performed. DIPG and glioblastoma cells were co-cultured with healthy donor macrophages, T cells, or natural killer (NK) cells, and flow cytometry and cytotoxicity assays performed to characterize the phenotype and function, respectively, of the immune cells. Results: DIPG tumors do not have increased macrophage or T-cell infiltration relative to nontumor control, nor do they overexpress immunosuppressive factors such as programmed death ligand 1 and/or transforming growth factor ß1. H3.3-K27M DIPG cells do not repolarize macrophages, but are not effectively targeted by activated allogeneic T cells. NK cells lysed all DIPG cultures. Conclusions: DIPG tumors have neither a highly immunosuppressive nor inflammatory microenvironment. Therefore, major considerations for the development of immunotherapy will be the recruitment, activation, and retention of tumor-specific effector immune cells.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Tronco Encefálico/imunologia , Glioma Pontino Intrínseco Difuso/imunologia , Imunidade Celular/imunologia , Imunoterapia , Microambiente Tumoral/imunologia , Adolescente , Adulto , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Estudos de Casos e Controles , Criança , Pré-Escolar , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/patologia , Glioma Pontino Intrínseco Difuso/terapia , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Prognóstico , Taxa de Sobrevida , Adulto JovemAssuntos
Antibacterianos/administração & dosagem , Neoplasias do Tronco Encefálico , Líquido da Lavagem Broncoalveolar/parasitologia , Infecções por Escherichia coli , Glioblastoma , Hospedeiro Imunocomprometido , Estrongiloidíase , Adulto , Animais , Antiparasitários/administração & dosagem , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/diagnóstico , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/imunologia , Glioblastoma/imunologia , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/parasitologia , Masculino , Strongyloides stercoralis/isolamento & purificação , Estrongiloidíase/diagnóstico , Estrongiloidíase/tratamento farmacológico , Estrongiloidíase/fisiopatologia , Resultado do TratamentoRESUMO
On the basis of immunological results, it is not in doubt that the immune system is able to recognize and eliminate transformed cells. A plethora of studies have investigated the immune system of patients with cancer and how it is prone to immunosuppression, due in part to the decrease in lymphocyte proliferation and cytotoxic activity. The series of experiments published following the demonstration by Dr Allison's group of the potential effect of anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) paved the way for a new perception in cancer immunotherapy: Immune checkpoints. Several T cellco-stimulatory molecules including cluster of differentiation (CD)28, inducible T cell co-stimulatory, 4-1BB, OX40, glucocorticoid-induced tumor necrosis factor receptor-related gene and CD27, and inhibitory molecules including T cell immunoglobulin and mucin domain-containing-3, programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), V-domain immunoglobulin suppressor of T cells activation, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, and B and T lymphocyte attenuator have been described in regulating T cell functions, and have been demonstrated to be essential targets in immunotherapy. In preclinical studies, glioblastoma multiforme, a high-grade glioma, the monotherapy targeting PD-1/PD-L1 and CTLA-4 resulted in increased survival times. An improved understanding of the pharmacodynamics and immune monitoring on glioma cancers, particularly in diffuse intrinsic pontine glioma (DIPG), an orphan type of cancer, is expected to have a major contribution to the development of novel therapeutic approaches. On the basis of the recent preclinical and clinical studies of glioma, but not of DIPG, the present review makes a claim for the importance of investigating the tumor microenvironment, the immune response and the use of immune checkpoints (agonists or antagonists) in preclinical/clinical DIPG samples by immune monitoring approaches and high-dimensional analysis. Evaluating the potential predictive and correlative biomarkers in preclinical and clinical studies may assist in answering certain crucial questions that may be useful to improve the clinical response in patients with DIPG.
Assuntos
Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma/tratamento farmacológico , Imunoterapia/métodos , Animais , Antineoplásicos Imunológicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Neoplasias do Tronco Encefálico/imunologia , Glioma/imunologia , Humanos , Monitorização ImunológicaRESUMO
Diffuse intrinsic pontine glioma (DIPG) is an incurable disease with a median overall survival of 10 months. Immune modulating antibodies have recently emerged as a highly promising treatment modality in multiple cancer types. We present results from the first study to evaluate the immune modulating antibody MDV9300 (pidilizumab) in pediatric patients with DIPG. All patients aged 3 years and older, diagnosed with DIPG between February 2014 and June 2015 in Israel, were offered to participate in the study. Enrolled patients were started on biweekly 6 mg/kg MDV9300 after radiation completion. Treatment was continued until disease progression on imaging. Patients were followed biweekly for the occurrence of neurological deficit toxicities and side effects. Secondary endpoints were event free survival and overall survival. Of 13 children diagnosed with DIPG during the study period, nine were enrolled in the study. The patients underwent radiotherapy and none had chemotherapy. A total of 83 cycles of MDV9300 (range 2-16) were applied. The main side effects were neutropenia (CTCAE grade 1-3), mild to moderate fatigue, and acute elevation of blood pressure. Four patients died within 1 year of the diagnosis, another three died within 2 years and two children are still alive nearly 30 months from diagnosis, with stable disease. The median event free survival is 9.3 months (range 6.8-24) and the median overall survival is 15.6 months (range 6.9-28). Preliminary results demonstrate that MDV9300 treatment is safe and may be effective in the treatment of children with DIPG.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma/tratamento farmacológico , Adolescente , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/radioterapia , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Feminino , Glioma/imunologia , Glioma/radioterapia , Humanos , Masculino , Intervalo Livre de Progressão , Estudos Prospectivos , Análise de SobrevidaRESUMO
PURPOSE: Diffuse brainstem gliomas (BSGs) and other high-grade gliomas (HGGs) of childhood carry a dismal prognosis despite current treatments, and new therapies are needed. Having identified a series of glioma-associated antigens (GAAs) commonly overexpressed in pediatric gliomas, we initiated a pilot study of subcutaneous vaccinations with GAA epitope peptides in HLA-A2-positive children with newly diagnosed BSG and HGG. PATIENTS AND METHODS: GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks. Primary end points were safety and T-cell responses against vaccine-targeted GAA epitopes. Treatment response was evaluated clinically and by magnetic resonance imaging. RESULTS: Twenty-six children were enrolled, 14 with newly diagnosed BSG treated with irradiation and 12 with newly diagnosed BSG or HGG treated with irradiation and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to dexamethasone and was associated with prolonged survival. Only two patients had progressive disease during the first two vaccine courses; 19 had stable disease, two had partial responses, one had a minor response, and two had prolonged disease-free status after surgery. Enzyme-linked immunosorbent spot analysis in 21 children showed positive anti-GAA immune responses in 13: to IL-13Rα2 in 10, EphA2 in 11, and survivin in three. CONCLUSION: GAA peptide vaccination in children with gliomas is generally well tolerated and has preliminary evidence of immunologic and clinical responses. Careful monitoring and management of pseudoprogression is essential.
Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Glioma/imunologia , Imunoterapia Ativa/métodos , Proteínas Inibidoras de Apoptose/imunologia , Indutores de Interferon/imunologia , Poli I-C/imunologia , Receptor EphA2/imunologia , Receptores de Interleucina-13/imunologia , Adolescente , Antígenos de Neoplasias/administração & dosagem , Neoplasias do Tronco Encefálico/imunologia , Vacinas Anticâncer/administração & dosagem , Carboximetilcelulose Sódica/farmacologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Portadores de Fármacos/farmacologia , ELISPOT , Epitopos , Feminino , Humanos , Imuno-Histoquímica , Lactente , Proteínas Inibidoras de Apoptose/administração & dosagem , Injeções Subcutâneas , Indutores de Interferon/administração & dosagem , Subunidade alfa1 de Receptor de Interleucina-13 , Estimativa de Kaplan-Meier , Lisina/farmacologia , Imageamento por Ressonância Magnética , Masculino , Poli I-C/administração & dosagem , Receptor EphA2/administração & dosagem , Receptores de Interleucina-13/administração & dosagem , Survivina , Adulto JovemRESUMO
Among 249 patients with teratoma-associated encephalitis, 211 had N-methyl-D-aspartate receptor antibodies and 38 were negative for these antibodies. Whereas antibody-positive patients rarely developed prominent brainstem-cerebellar symptoms, 22 (58%) antibody-negative patients developed a brainstem-cerebellar syndrome, which in 45% occurred with opsoclonus. The median age of these patients was 28.5 years (range = 12-41), 91% were women, and 74% had full recovery after therapy and tumor resection. These findings uncover a novel phenotype of paraneoplastic opsoclonus that until recently was likely considered idiopathic or postinfectious. The triad of young age (teenager to young adult), systemic teratoma, and high response to treatment characterize this novel brainstem-cerebellar syndrome.
Assuntos
Neoplasias do Tronco Encefálico/imunologia , Encefalite/complicações , Encefalite/terapia , Transtornos da Motilidade Ocular/complicações , Teratoma/complicações , Adulto , Autoanticorpos/imunologia , Neoplasias do Tronco Encefálico/complicações , Neoplasias do Tronco Encefálico/cirurgia , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/cirurgia , Criança , Encefalite/imunologia , Feminino , Humanos , Masculino , Transtornos da Motilidade Ocular/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Avaliação de Sintomas , Síndrome , Teratoma/imunologia , Teratoma/cirurgiaAssuntos
Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Sistema Nervoso Central/imunologia , Linfoma não Hodgkin/imunologia , Imageamento por Ressonância Magnética/métodos , Neoplasias do Tronco Encefálico/complicações , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Humanos , Imunocompetência , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/patologia , Pessoa de Meia-IdadeAssuntos
Antígenos/imunologia , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/patologia , Encefalite/imunologia , Encefalite/patologia , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/patologia , Adulto , Antígenos/líquido cefalorraquidiano , Neoplasias do Tronco Encefálico/líquido cefalorraquidiano , Encefalite/líquido cefalorraquidiano , Feminino , Humanos , Imageamento por Ressonância Magnética , Síndromes Paraneoplásicas do Sistema Nervoso/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Remissão Espontânea , Tomografia Computadorizada por Raios XRESUMO
A major focus of tumor immunology is to reveal the potential role and capacity of immunocompetent cells found in different solid tumor tissues. The most abundant infiltrating cells (TIL), the T lymphocytes have been investigated in details concerning T-cell receptor usage and specificity. However, B cells have hardly been investigated in this respect, although high cellular B-cell infiltration has been correlated with improved patients' survival in some breast carcinomas. This led to our objectives to study variable region gene usage of the tumor-infiltrating B cells in different breast carcinoma types. By defining the immunoglobulin repertoire of the tumor-infiltrating B lymphocytes in the most common invasive ductal carcinoma (IDC) of the breast we compared it to the rare medullary breast carcinoma (MBC). After phenotyping infiltrating ductal carcinomas, B cells were obtained from tumor tissue by microdissection technique. Numerous rearranged TIL-B immunoglobulin heavy chain V genes (VH) were amplified, cloned, sequenced, and comparatively analyzed. Some characteristics were found for both breast carcinoma types. The immunoglobulins produced by TIL-B in ductal carcinoma are highly matured and oligoclonal. We conclude that Ig variable region gene usage reveals similar and distinguishable characteristics of TIL-B immunoglobulin repertoires, which are representative of the nature of the immune responses in invasive ductal and medullary breast carcinomas.
Assuntos
Linfócitos B/imunologia , Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/imunologia , Genes de Imunoglobulinas , Região Variável de Imunoglobulina/genética , Linfócitos do Interstício Tumoral/imunologia , Invasividade Neoplásica/patologia , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/patologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Humanos , Estudos RetrospectivosRESUMO
Diffuse type brainstem glioma is one of the most malignant types of brain tumors and the prognosis is extremely poor. The proliferative potential of these tumors is presumed to be very high, but there is little information about the cell kinetics of brainstem glioma because surgical resection is rarely performed. The histological grade, tumor spread, growth potential, and prognosis were evaluated in 40 autopsy cases of diffuse type brainstem glioma. To quantify the growth potentials of individual tumors, the proliferating cell indices of Ki-67 (MIB-1) and proliferating cell nuclear antigen (PCNA) monoclonal antibodies were measured. Mean MIB-1 and PCNA proliferating cell indices were 20.4% (24 cases) and 37.0% (28 cases), respectively, in 34 glioblastomas. The median survival time was 40 weeks in 22 treated patients. The mean PCNA proliferating cell index was 10.8% in four of five anaplastic astrocytomas and the median survival time in four treated patients was 91 weeks. The MIB-1 and PCNA proliferating cell indices of one astrocytoma were 2.9% and 20.3%, respectively, and the survival time was 56 weeks. The overall median survival time was 32 weeks. There was a significant difference in PCNA proliferating cell indices between glioblastomas and anaplastic astrocytomas (p < 0.05) and there was a significant difference in survival time between glioblastomas (40 weeks) and anaplastic astrocytomas plus astrocytoma (74 weeks) among the treated patients (p < 0.05). Supratentorial extension was more frequent in glioblastomas than in anaplastic astrocytomas (p < 0.05). Our results suggest that the majority of diffuse type brainstem gliomas are glioblastoma and the proliferative potential is probably as high as that of adult supratentorial glioblastoma. Supratentorial extension and dissemination are relatively frequent in the advanced stage. Anaplastic astrocytoma or astrocytoma is rarer and less infiltrative and proliferative, and carries a slightly better prognosis than glioblastoma.