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Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
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Imunoterapia , Lipídeos , RNA , Microambiente Tumoral , Animais , Cães , Feminino , Humanos , Camundongos , Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Glioblastoma/terapia , Glioblastoma/imunologia , Glioma/terapia , Glioma/imunologia , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Neoplasias/imunologia , RNA/química , RNA/uso terapêutico , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Lipídeos/químicaRESUMO
INTRODUCTION: Brain tumors remain especially challenging to treat due to the presence of the blood-brain barrier. The unique biophysical properties of nanomaterials enable access to the tumor environment with minimally invasive injection methods such as intranasal and systemic delivery. METHODS: In this review, we will discuss approaches taken in NP delivery to brain tumors in preclinical neuro-oncology studies and ongoing clinical studies. RESULTS: Despite recent development of many promising nanoparticle systems to modulate immunologic function in the preclinical realm, clinical work with nanoparticles in malignant brain tumors has largely focused on imaging, chemotherapy, thermotherapy and radiation. CONCLUSION: Review of early preclinical studies and clinical trials provides foundational safety, feasibility and toxicology data that can usher a new wave of nanotherapeutics in application of immunotherapy and translational oncology for patients with brain tumors.
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Neoplasias Encefálicas , Nanopartículas , Adjuvantes Imunológicos/uso terapêutico , Barreira Hematoencefálica , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Humanos , Fatores Imunológicos/uso terapêuticoRESUMO
Translation of nanoparticles (NPs) into human clinical trials for patients with refractory cancers has lagged due to unknown biologic reactivities of novel NP designs. To overcome these limitations, simple well-characterized mRNA lipid-NPs have been developed as cancer immunotherapeutic vaccines. While the preponderance of RNA lipid-NPs encoding for tumor-associated antigens or neoepitopes have been designed to target lymphoid organs, they remain encumbered by the profound intratumoral and systemic immunosuppression that may stymie an activated T cell response. Herein, we show that systemic localization of untargeted tumor RNA (derived from whole transcriptome) encapsulated in lipid-NPs, with excess positive charge, primes the peripheral and intratumoral milieu for response to immunotherapy. In immunologically resistant tumor models, these RNA-NPs activate the preponderance of systemic and intratumoral myeloid cells (characterized by coexpression of PD-L1 and CD86). Addition of immune checkpoint inhibitors (ICIs) (to animals primed with RNA-NPs) augments peripheral/intratumoral PD-1+CD8+ cells and mediates synergistic antitumor efficacy in settings where ICIs alone do not confer therapeutic benefit. These synergistic effects are mediated by type I interferon released from plasmacytoid dendritic cells (pDCs). In translational studies, personalized mRNA-NPs were safe and active in a client-owned canine with a spontaneous malignant glioma. In summary, we demonstrate widespread immune activation from tumor loaded RNA-NPs concomitant with inducible PD-L1 expression that can be therapeutically exploited. While immunotherapy remains effective for only a subset of cancer patients, combination therapy with systemic immunomodulating RNA-NPs may broaden its therapeutic potency.
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Glioma/tratamento farmacológico , Imunoterapia , Lipídeos/administração & dosagem , Nanopartículas/administração & dosagem , Medicina de Precisão , Animais , Antígeno B7-2/antagonistas & inibidores , Antígeno B7-2/genética , Antígeno B7-2/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Modelos Animais de Doenças , Cães , Glioma/imunologia , Glioma/patologia , Glioma/veterinária , Humanos , Lipídeos/química , Lipídeos/imunologia , Ativação Linfocitária/imunologia , Nanopartículas/química , RNA Neoplásico/química , RNA Neoplásico/genética , RNA Neoplásico/imunologia , Transcriptoma/genéticaRESUMO
Antibody-based immune checkpoint blockade therapy has revolutionized the field of cancer immunotherapy, yet its efficacy remains limited in immunologically cold tumors. Combining checkpoint inhibitors with costimulatory agonists improves tumoricidal activity of T cells but also can lead to off-target hepatotoxicity. Although bispecific antibodies confer tumor selectivity to alleviate undesirable adverse effects, toxicity concerns persist with increased dosing. In this issue of Cancer Research, Yuwen and colleagues introduce ATG-101, a tetravalent PD-L1×4-1BB bispecific antibody with high programmed death ligand 1 (PD-L1) affinity and low 4-1BB affinity, aiming to mitigate hepatotoxicity. ATG-101 demonstrates PD-L1-dependent 4-1BB activation, leading to selective T-cell activation within the tumor microenvironment. ATG-101 exhibits potent antitumor activity, even in large, immunologically cold, and monotherapy-resistant tumor models. Single-cell RNA sequencing reveals significant shifts of immune cell populations in the tumor microenvironment from protumor to antitumor phenotypes following ATG-101 treatment. In cynomolgus monkeys, no serious cytokine storm and hepatotoxicity are observed after ATG-101 treatment, indicating a broad therapeutic window for ATG-101 in cancer treatment. This study highlights the potential of tetravalent bispecific antibodies in cancer immunotherapy, with implications for various antibody-based treatment modalities across different fields. See related article by Yuwen et al., p. 1680.
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Anticorpos Biespecíficos , Antígeno B7-H1 , Animais , Humanos , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Macaca fascicularis , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
Cell-based therapies are revolutionizing medicine by replacing or modifying dysfunctional cells with healthy cells or engineered derivatives, offering disease reversal and cure. One promising approach is using cell-derived extracellular vesicles (EVs), which offer therapeutic benefits similar to cell transplants without the biosafety risks. Although EV applications face challenges like limited production, inadequate therapeutic loading, and poor targeting efficiency, recent advances in bioengineering have enhanced their effectiveness. Herein, we summarize technological breakthroughs in EV bioengineering over the past 5 years, highlighting their improved therapeutic functionalities and potential clinical prospects. We also discuss biomanufacturing processes, regulation, and safety considerations for bioengineered EV therapies, emphasizing the significance of establishing robust frameworks to ensure translation capability, safety, and therapeutic effectiveness for successful clinical adoption.
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Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.
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Barreira Hematoencefálica , Encéfalo , Circulação Cerebrovascular , Nanopartículas , Alcaloides de Vinca , Animais , Alcaloides de Vinca/farmacologia , Alcaloides de Vinca/farmacocinética , Alcaloides de Vinca/administração & dosagem , Alcaloides de Vinca/química , Nanopartículas/química , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Camundongos , Circulação Cerebrovascular/efeitos dos fármacos , Masculino , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Humanos , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Camundongos Endogâmicos C57BL , Distribuição Tecidual , Sistemas de Liberação de Medicamentos , Camundongos TransgênicosRESUMO
There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation. Herein, we develop a recombinant adeno-associated virus (AAV) gene therapy that enables focal and stable reconstitution of the tumor microenvironment with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for lymphocytes. By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by cytotoxic lymphocytes, sensitizing glioblastoma to anti-PD-1 immune checkpoint blockade in female preclinical tumor models. These effects are accompanied by immunologic signatures evocative of an inflamed tumor microenvironment. These findings support AAV gene therapy as an adjuvant for reconditioning glioblastoma immunogenicity given its safety profile, tropism, modularity, and off-the-shelf capability.
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Quimiocina CXCL9 , Dependovirus , Terapia Genética , Glioblastoma , Inibidores de Checkpoint Imunológico , Receptor de Morte Celular Programada 1 , Microambiente Tumoral , Glioblastoma/terapia , Glioblastoma/imunologia , Dependovirus/genética , Microambiente Tumoral/imunologia , Animais , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Camundongos , Terapia Genética/métodos , Feminino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linhagem Celular Tumoral , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genéticaRESUMO
INTRODUCTION: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. METHODS: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. RESULTS: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR. DISCUSSION AND CONCLUSIONS: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.
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Neoplasias Pancreáticas , Dosagem Radioterapêutica , Humanos , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Masculino , Feminino , Estados Unidos/epidemiologia , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso de 80 Anos ou maisRESUMO
Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses.
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Células Apresentadoras de Antígenos , Imunidade Inata , Peptídeos , Animais , Imunidade Inata/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , Camundongos , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/efeitos dos fármacos , Humanos , Feminino , Cátions/química , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Receptor Toll-Like 9/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/químicaRESUMO
Diencephalic tumors tend to be low grade tumors located near several critical structures, including the optic nerves, optic chiasm, pituitary, hypothalamus, Circle of Willis, and hippocampi. In children, damage to these structures can impact physical and cognitive development over time. Thus, the goal of radiotherapy is to maximize long term survival while minimizing late effects, including endocrine disruption leading to precocious puberty, height loss, hypogonadotropic hypogonadism, and primary amenorrhea; visual disruption including blindness; and vascular damage resulting in cerebral vasculopathy. Compared to photon therapy, proton therapy offers the potential to decrease unnecessary dose to these critical structures while maintaining adequate dose to the tumor. In this article, we review the acute and chronic toxicities associated with radiation for pediatric diencephalic tumors, focusing on the use of proton therapy to minimize treatment-related morbidity. Emerging strategies to further reduce radiation dose to critical structures will also be considered.
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Purpose: The immune system's role in mediating the cytotoxic effects of chemoradiotherapy remains not completely understood. The integration of immunotherapies into treatment will require insight into features and timing of the immune microenvironment associated with treatment response. Here, we investigated the role of circulating neutrophils and tumor-associated myeloid cells (TSAMs) as potential agents and biomarkers for disease-related outcomes in locally advanced cervical cancer (LACC). Material and Methods: Hematologic parameters for two LACC patient cohorts, a retrospective clinical and a prospective translational cohort, were obtained at baseline, weekly during chemoradiotherapy for the retrospective cohort, biweekly during chemoradiotherapy for the prospective cohort, and at the first follow-up visit for both cohorts (mean 14.7 weeks, range 8.1-25.1 weeks for the prospective cohort and 5.3 weeks with a range of 2.7-9.0 weeks for the retrospective cohort). In both cohorts, baseline as well as mean and lowest on-treatment values for platelets, hemoglobin, absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) were analyzed for correlations with disease-related outcomes. In the prospective cohort, circulating myeloid cells were isolated from peripheral blood mononuclear cells (PBMCs), and TSAMs were isolated from tumor tissue via a novel serial cytobrush sampling assay. The samples were analyzed by flow cytometry. Results: In both cohorts, the only hematologic parameter significantly associated with survival was elevated on-treatment mean ANC (mANC), which was associated with lower local failure-free and overall survival rates in the retrospective and prospective cohorts, respectively. mANC was not associated with a difference in distant metastases. CD11b+CD11c- TSAMs, which act as a surrogate marker for intratumoral neutrophils, steadily decreased during the course of chemoRT and nadier'd at week 5 of treatment. Conversely, circulating myeloid cells identified from PBMCs steadily increased through week 5 of treatment. Regression analysis confirmed an inverse relationship between circulating myeloid cells and TSAMs at this time point. Conclusions: These findings identify on-treatment mean neutrophil count as a predictor of disease-related outcomes, suggest that neutrophils contribute to chemoradiation treatment resistance, and demonstrate the importance of techniques to measure intratumoral immune activity.
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The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.
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Vesículas Extracelulares , Glioblastoma , Humanos , RNA Mensageiro/genética , Imunoterapia/métodos , Vesículas Extracelulares/genética , EletroporaçãoRESUMO
Messenger RNA (mRNA) has emerged as a remarkable tool for COVID-19 prevention but its use for induction of therapeutic cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Herein, we develop a facile approach for substantially enhancing immunogenicity of tumor-derived mRNA in lipid-particle (LP) delivery systems. By using mRNA as a molecular bridge with ultrapure liposomes and foregoing helper lipids, we promote the formation of 'onion-like' multi-lamellar RNA-LP aggregates (LPA). Intravenous administration of RNA-LPAs mimics infectious emboli and elicits massive DC/T cell mobilization into lymphoid tissues provoking cancer immunogenicity and mediating rejection of both early and late-stage murine tumor models. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for toll-like receptor engagement, RNA-LPAs stimulate intracellular pathogen recognition receptors (RIG-I) and reprogram the TME thus enabling therapeutic T cell activity. RNA-LPAs were safe in acute/chronic murine GLP toxicology studies and immunologically active in client-owned canines with terminal gliomas. In an early phase first-in-human trial for patients with glioblastoma, we show that RNA-LPAs encoding for tumor-associated antigens elicit rapid induction of pro-inflammatory cytokines, mobilization/activation of monocytes and lymphocytes, and expansion of antigen-specific T cell immunity. These data support the use of RNA-LPAs as novel tools to elicit and sustain immune responses against poorly immunogenic tumors.
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Although respirators and filters are designed to prevent the spread of pathogenic aerosols, a stockpile shortage is anticipated during the next flu pandemic. Contact transfer and reaerosolization of collected microbes from used respirators are also a concern. An option to address these potential problems is UV irradiation, which inactivates microbes by dimerizing thymine/uracil in nucleic acids. The objective of this study was to determine the effects of transmission mode and environmental conditions on decontamination efficiency by UV. In this study, filters were contaminated by different transmission pathways (droplet and aerosol) using three spraying media (deionized water [DI], beef extract [BE], and artificial saliva [AS]) under different humidity levels (30% [low relative humidity {LRH}], 60% [MRH], and 90% [HRH]). UV irradiation at constant intensity was applied for two time intervals at each relative humidity condition. The highest inactivation efficiency (IE), around 5.8 logs, was seen for DI aerosols containing MS2 on filters at LRH after applying a UV intensity of 1.0 mW/cm(2) for 30 min. The IE of droplets containing MS2 was lower than that of aerosols containing MS2. Absorption of UV by high water content and shielding of viruses near the center of the aggregate are considered responsible for this trend. Across the different media, IEs in AS and in BE were much lower than in DI for both aerosol and droplet transmission, indicating that solids present in AS and BE exhibited a protective effect. For particles sprayed in a protective medium, RH is not a significant parameter.
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Aerossóis , Filtros de Ar/virologia , Descontaminação/métodos , Levivirus/isolamento & purificação , Levivirus/efeitos da radiação , Raios Ultravioleta , Umidade , Fatores de TempoRESUMO
In the event of a pandemic, the general public would use filters as protective devices. However, most commercial filters only remove airborne viruses physically without inactivating them, allowing reproduction on the surface and yielding the mask as a fomite. The objective of this study was to investigate the inactivation performance of dialdehyde starch (DAS) treated filters against airborne viruses. The viable removal efficiency by and relative survivability on the biocidal filters prepared with dialdehyde starch compared to untreated filters were investigated using MS2 bacteriophage at high relative humidity (80-90%) and room temperature. Experimental results showed no significant difference in viable removal efficiency and pressure drop between the treated and untreated filters for polypropylene filtering facepiece respirators. The pressure drop of DAS treated cellulose filters significantly decreased although there was no significant change in viable removal efficiency; the combination of these two factors resulted in an increase of filter quality. All biocidal filters showed a significantly lower relative survivability than untreated filters, and the relative survivability decreased as the concentration of DAS increased. The biocidal filter treated with 4% DAS presented an average of 30% survivability compared to the baseline of untreated filters. The results demonstrate that dialdehyde starch can be incorporated onto filters to provide an effective means for inactivating MS2 viruses through surface contact.
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PURPOSE: Few studies report outcomes in children treated with radiation for nonmyxopapillary ependymoma of the spinal cord, and little evidence exists to inform decisions regarding target volume and prescription dose. Moreover, virtually no mature outcome data exist on proton therapy for this tumor. We describe our combined institutional experience treating pediatric classical/anaplastic ependymoma of the spinal cord with proton therapy. METHODS AND MATERIALS: Between 2008 and 2019, 14 pediatric patients with nonmetastatic nonmyxopapillary grade II (n = 6) and grade III (n = 8) spinal ependymoma received proton therapy. The median age at radiation was 14 years (range, 1.5-18 years). Five tumors arose within the cervical cord, 3 within the thoracic cord, and 6 within the lumbosacral cord. Before radiation therapy, 3 patients underwent subtotal resection, and 11 underwent gross-total or near total resection. Two patients received chemotherapy. For radiation, the clinical target volume received 50.4 Gy (n = 8), 52.2 (n = 1), or 54 Gy (n = 5), with the latter receiving a boost to the gross tumor volume after the initial 50.4 Gy, modified to respect spinal cord tolerance. RESULTS: With a median follow-up of 6.3 years (range, 1.5-14.8 years), no tumors progressed. Although most patients experienced neurologic sequela after surgery, only 1 developed additional neurologic deficits after radiation: An 18-year-old male who received 54 Gy after gross total resection of a lumbosacral tumor developed grade 2 erectile dysfunction. There were 2 cases of musculoskeletal toxicity attributable to surgery and radiation. At analysis, no patient had developed cardiac, pulmonary, or other visceral organ complications or a second malignancy. CONCLUSION: Radiation to a total dose of 50 to 54 Gy can be safely delivered and plays a beneficial role in the multidisciplinary management of children with nonmyxopapillary spinal cord ependymoma. Proton therapy may reduce late radiation effects and is not associated with unexpected spinal cord toxicity.
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Ependimoma , Terapia com Prótons , Neoplasias da Medula Espinal , Adolescente , Criança , Pré-Escolar , Ependimoma/patologia , Humanos , Lactente , Masculino , Terapia com Prótons/efeitos adversos , Terapia com Prótons/métodos , Estudos Retrospectivos , Medula Espinal/efeitos da radiação , Neoplasias da Medula Espinal/radioterapia , Neoplasias da Medula Espinal/cirurgia , Resultado do TratamentoRESUMO
Anti-VEGF therapy prolongs recurrence-free survival in patients with glioblastoma but does not improve overall survival. To address this discrepancy, we investigated immunologic resistance mechanisms to anti-VEGF therapy in glioma models. A screening of immune-associated alterations in tumors after anti-VEGF treatment revealed a dose-dependent upregulation of regulatory T-cell (Treg) signature genes. Enhanced numbers of Tregs were observed in spleens of tumor-bearing mice and later in tumors after anti-VEGF treatment. Elimination of Tregs with CD25 blockade before anti-VEGF treatment restored IFNγ production from CD8+ T cells and improved antitumor response from anti-VEGF therapy. The treated tumors overexpressed the glutamate/cystine antiporter SLC7A11/xCT that led to elevated extracellular glutamate in these tumors. Glutamate promoted Treg proliferation, activation, suppressive function, and metabotropic glutamate receptor 1 (mGlutR1) expression. We propose that VEGF blockade coupled with glioma-derived glutamate induces systemic and intratumoral immunosuppression by promoting Treg overrepresentation and function, which can be pre-emptively overcome through Treg depletion for enhanced antitumor effects. SIGNIFICANCE: Resistance to VEGF therapy in glioblastoma is driven by upregulation of Tregs, combined blockade of VEGF, and Tregs may provide an additive antitumor effect for treating glioblastoma.
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Bevacizumab/farmacologia , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/imunologia , Ácido Glutâmico/metabolismo , Linfócitos T Reguladores/imunologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/metabolismo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/imunologiaRESUMO
PURPOSE: Immunotherapy has been demonstrably effective against multiple cancers, yet tumor escape is common. It remains unclear how brain tumors escape immunotherapy and how to overcome this immune escape. EXPERIMENTAL DESIGN: We studied KR158B-luc glioma-bearing mice during treatment with adoptive cellular therapy (ACT) with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T-cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. In addition, programmed cell death protein-1 (PD-1) checkpoint blockade was studied in combination with ACT. RESULTS: Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of MHC class I, and upregulation of checkpoint molecules. Polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60%. The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon natural killer cells and T cells. CONCLUSIONS: These findings suggest that the immune landscape of brain tumors are markedly different postimmunotherapy yet can still be targeted with immunotherapy.
Assuntos
Glioma/terapia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Evasão Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Glioma/genética , Glioma/imunologia , Glioma/patologia , Xenoenxertos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia Adotiva/efeitos adversos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: The immunomodulatory effects of statins on vaccine response remain uncertain. Therefore, the objective of this study was to determine if atorvastatin enhances pneumococcal-specific antibody titer following 23-valent pneumococcal polysaccharide vaccination. METHODS: Double-blind, placebo-controlled, single-center randomized clinical trial entitled StatVax. Subjects were enrolled between June and July 2014 and followed up through September 2014. 33 healthy volunteers signed informed consent after volunteer sampling. 11 participants were excluded; 22 healthy volunteers without prior pneumococcal vaccination were enrolled and completed the study. Participants were randomized to receive a 28-day course of 40â¯mg atorvastatin (nâ¯=â¯12) or matching lactose placebo (nâ¯=â¯10). On day 7 of treatment, Pneumovax 23 was administered intramuscularly. The primary outcome was fold change in total pneumococcal-specific antibody titer determined by a ratio of post-vaccination titer over baseline titer. Secondary outcomes included serotype-specific pneumococcal antibody titer, seroconversion, complete blood counts (CBC), erythrocyte sedimentation rate (ESR), and serum cytokine analysis. RESULTS: Of the 22 randomized patients (mean age, 23.86; SD, 4.121; 11 women [50%]), 22 completed the trial. Total anti-pneumococcal antibody titer in the atorvastatin group went from a baseline mean of 32.58 (SD, 15.96) to 147.7 (SD, 71.52) µg/mL at 21â¯days post-vaccination while titer in the placebo group went from a mean of 30.81 (SD, 13.04) to 104.4 (SD, 45) µg/mL. When comparing fold change between treatment groups, there was a significant increase in fold change of total anti-pneumococcal antibody titer in the atorvastatin group compared to the placebo group (2-way ANOVA, pâ¯=â¯.0177). CONCLUSIONS: Atorvastatin enhances antigen-specific primary humoral immune response to a T cell-independent pneumonia vaccination. Pending confirmation by larger cohort studies of target populations, peri-vaccination conventional doses of statins can become a novel adjuvant for poorly-immunogenic polysaccharide-based vaccines. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02097589.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Anticorpos Antibacterianos/sangue , Anticolesterolemiantes/imunologia , Atorvastatina/imunologia , Imunidade Humoral , Vacinas Pneumocócicas/imunologia , Adulto , Formação de Anticorpos , Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Citocinas/sangue , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Vacinas Pneumocócicas/administração & dosagem , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/prevenção & controle , Streptococcus pneumoniae , Vacinação , Adulto JovemRESUMO
While promising, immunotherapy has yet to be fully unlocked for the preponderance of cancers where conventional chemoradiation reigns. This remains particularly evident in pediatric sarcomas where standard of care has not appreciably changed in decades. Importantly, pediatric bone sarcomas, like osteosarcoma and Ewing's sarcoma, possess unique tumor microenvironments driven by distinct molecular features, as do rhabdomyosarcomas and soft tissue sarcomas. A better understanding of each malignancy's biology, heterogeneity, and tumor microenvironment may lend new insights toward immunotherapeutic targets in novel platform technologies for cancer vaccines and adoptive cellular therapy. These advances may pave the way toward new treatments requisite for pediatric sarcomas and patients in need of new therapies.