RESUMEN

Cancer immunotherapies strive to overcome tumor-induced immune suppression and activate antitumor immune responses. Although cytotoxic T lymphocytes (CTLs) play a pivotal role in this process, natural killer (NK) cells have also demonstrated remarkable tumor-killing abilities, given their ability to discriminate tumor cells from normal cells and mediate specific antitumoral cytotoxicity. NK cells activation depends on a balance between activation and inhibition signals from several ligands/receptors. Among them, MICA/NKG2D axis is a master regulator of NK activation. MHC class I chain-related polypeptide A (MICA) expression is upregulated by many tumor cell lines and primary tumors and serves as a ligand for the activating NK group 2D (NKG2D) receptor on NK cells and subpopulations of T cells. However, cancer cells can cleave MICA, making it soluble and de-targeting tumor cells from NK cells, leading to tumor immune escape.In this study, we present ICOVIR15KK-MICAMut, an oncolytic adenovirus (OAdv) armed with a transgene encoding a non-cleavable MICA to promote NK-mediated cell-killing capacity and activate the immune response against cancer cells. We first demonstrated the correct MICA overexpression from infected cells. Moreover, our MICA-expressing OAdv promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells. Finally, OAdv-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control.In summary, this study highlights the significance of NK cells in cancer immunotherapy and presents an innovative approach using a modified oncolytic virus to enhance NK cell activation and antitumor immune response. These findings suggest promising potential for future research and clinical applications.

Asunto(s)

Adenoviridae , Subfamilia K de Receptores Similares a Lectina de Células NK , Humanos , Animales , Ratones , Adenoviridae/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Activación de Linfocitos , Genes MHC Clase I , Escape del Tumor

RESUMEN

BACKGROUND: Chronic pelvic pain syndrome (CPPS) is a multifactorial disorder that affects 5.7% to 26.6% of women and 2.2% to 9.7% of men, characterized by hypersensitivity of the central and peripheral nervous system affecting bladder and genital function. People with CPPS have much higher rates of psychological disorders (anxiety, depression, and catastrophizing) that increase the severity of chronic pain and worsen quality of life. Myofascial therapy, manual therapy, and treatment of trigger points are proven therapeutic options for this syndrome. This study aims to evaluate the efficacy of capacitive resistive monopolar radiofrequency (CRMRF) at 448 kHz as an adjunct treatment to other physiotherapeutic techniques for reducing pain and improving the quality of life of patients with CPPS. METHODS: This triple-blind (1:1) randomized controlled trial will include 80 women and men with CPPS. Participants will be randomized into a CRMRF activated group or a CRMRF deactivated group and receive physiotherapeutic techniques and pain education. The groups will undergo treatment for 10 consecutive weeks. At the beginning of the trial there will be an evaluation of pain intensity (using VAS), quality of life (using the SF-12), kinesiophobia (using the TSK-11), and catastrophism (using the PCS), as well as at the sixth and tenth sessions. DISCUSSION: The results of this study will show that CRMRF benefits the treatment of patients with CPPS, together with physiotherapeutic techniques and pain education. These results could offer an alternative conservative treatment option for these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03797911 . Registered on 8 January 2019.

Asunto(s)

Dolor Crónico , Dolor Crónico/diagnóstico , Dolor Crónico/terapia , Femenino , Humanos , Masculino , Dimensión del Dolor , Dolor Pélvico/diagnóstico , Dolor Pélvico/terapia , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Síndrome

RESUMEN

BACKGROUND: Radical prostatectomy is the gold standard treatment for men with localized prostate cancer. This technique is associated with post-operative urinary incontinence. Pelvic floor physiotherapy is a conservative, painless and economical treatment for this specific situation. Kegel exercises and perineal electrostimulation are common techniques to train pelvic floor muscles. The perineal electrostimulation can be applied to the patient with surface electrodes or by an intra-cavitary anal probe. This study proposes that transcutaneous perineal electrostimulation is as effective as intra-cavitary electrostimulation in reducing urinary incontinence secondary to radical prostatectomy. The main objective is to compare the efficacy of the treatment with transcutaneous perineal electrostimulation versus the same intra-cavitary treatment to reduce the magnitude of urinary incontinence after radical prostatectomy, and the impact on the quality of life. METHODS: This single-blind equivalence randomized controlled trial will include 70 man who suffer urinary incontinence post radical prostatectomy. Participants will be randomized into surface electrodes group and intra-anal probe group. The groups will receive treatment for 10 consecutive weeks. Outcomes include changes in the 24-h Pad Test, and ICIQ-SF, SF-12 and I-QoL questionnaires. Clinical data will be collected at baseline, 6 and 10 weeks after the first session, and 6 months after the end of treatment. DISCUSSION: The results will allow us to prescribe the most beneficial perineal electrostimulation technique in the treatment of urinary incontinence derived from radical prostatectomy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03587402. 27/06/2018.

Asunto(s)

Terapia por Estimulación Eléctrica/métodos , Complicaciones Posoperatorias/terapia , Prostatectomía , Neoplasias de la Próstata/cirugía , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Incontinencia Urinaria/terapia , Estudios de Equivalencia como Asunto , Humanos , Masculino , Perineo , Prostatectomía/métodos , Método Simple Ciego , Estimulación Eléctrica Transcutánea del Nervio , Resultado del Tratamiento

RESUMEN

Antitumor efficacy of systemically administered oncolytic adenoviruses (OAdv) is limited due to diverse factors such as liver sequestration, neutralizing interactions in blood, elimination by the immune system, and physical barriers in tumors. It is therefore of clinical relevance to improve OAdv bioavailability and tumor delivery. Among the variety of tumor-targeting strategies, the use of stem cells and specifically bone marrow-derived mesenchymal stem cells (BM-MSCs) is of particular interest due to their tumor tropism and immunomodulatory properties. Nonetheless, the invasive methods to obtain these cells, the low number of MSCs present in the bone marrow, and their restricted in vitro expansion represent major obstacles for their use in cancer treatments, pointing out the necessity to identify an alternative source of MSCs. Here, we have evaluated the use of menstrual blood-derived mesenchymal stem cells (MenSCs) as cell carriers for regional delivery of an OAdv in the tumor. Our results indicate that MenSCs can be isolated without invasive methods, they have an increased proliferation rate compared to BM-MSCs, and they can be efficiently infected with different serotype 5-based capsid-modified adenoviruses, leading to viral replication and release. In addition, our in vivo studies confirmed the tumor-homing properties of MenSCs after regional administration.

RESUMEN

CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.

Asunto(s)

Ligando de CD40/genética , Endotelio Vascular/inmunología , Terapia Genética , Células Mieloides/inmunología , Virus Oncolíticos/genética , Neoplasias Pancreáticas/terapia , Linfocitos T Citotóxicos/inmunología , Animales , Movimiento Celular/inmunología , Citocinas/metabolismo , Células Dendríticas/inmunología , Femenino , Vectores Genéticos/administración & dosificación , Humanos , Ratones , Ratones Endogámicos C57BL , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Células Tumorales Cultivadas , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

There is great skepticism in the capability of adenovirus vectors and oncolytic adenoviruses to reach specific organs or tumors upon systemic administration. Besides antibodies, the presence of CAR (coxsackie and adenovirus receptor) in human erythrocytes has been postulated to sequester CAR-binding adenoviruses, commonly used in gene therapy and oncolytic applications. The use of non-CAR-binding fibers or serotypes has been postulated to solve this limitation. Given the lack of integrins in erythrocytes and therefore of internalization of the CAR-bound virus, we hypothesized that the interaction of adenovirus type 5 (Ad5) with CAR in human erythrocytes could be reversible. In this work, we have studied the effects of Ad5 interaction with human erythrocytes via CAR. Although erythrocyte binding was observed, it did not reduce viral transduction of tumor cells in vitro after long-term incubations. Transplantation of human erythrocytes into nude mice did not reduce Ad5 extravasation and transduction of liver and human xenograft tumors after systemic administration. These findings indicate that despite human erythrocytes are able to bind to Ad5, this binding is reversible and does not prevent extravasation and organ transduction after systemic delivery. Thus, the poor bioavailability of systemically delivered CAR-binding adenoviruses in humans is likely due to other factors such as liver sequestration or neutralizing antibodies.

Asunto(s)

Adenoviridae/fisiología , Proteína de la Membrana Similar al Receptor de Coxsackie y Adenovirus/metabolismo , Eritrocitos/metabolismo , Eritrocitos/virología , Transducción Genética , Acoplamiento Viral , Infecciones por Adenoviridae/metabolismo , Infecciones por Adenoviridae/virología , Adenovirus Humanos/fisiología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Ratones , Internalización del Virus

RESUMEN

Oncolytic adenoviruses can promote immune responses against tumors by expressing and/or displaying tumor-associated antigens. However, the strong immunodominance of viral antigens mask responses against tumor epitopes. In addition, defects in major histocompatibility complex class I antigen presentation pathway such as the downregulation of the transporter-associated with antigen processing (TAP) are frequently associated with immune evasion of tumor cells. To promote the immunogenicity of exogenous epitopes in the context of an oncolytic adenovirus, we have taken advantage of the ER localization of the viral protein E3-19K. We have inserted tumor-associated epitopes after the N-terminal signal sequence for membrane insertion of this protein and flanked them with linkers cleavable by the protease furin to facilitate their TAP-independent presentation. This strategy allowed an enhanced presentation of the exogenous epitopes in TAP-deficient tumor cells in vitro and the generation of higher specific immune responses in vivo that were able to significantly control tumor growth.

Asunto(s)

Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas E3 de Adenovirus/genética , Adenovirus Humanos/genética , Epítopos/genética , Mutagénesis Insercional , Neoplasias/terapia , Virus Oncolíticos/genética , Adenovirus Humanos/metabolismo , Animales , Presentación de Antígeno , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Ratones Endogámicos C57BL

RESUMEN

Endovenously administered oncolytic viruses extravasate and penetrate poorly into tumors. iRGD is a cyclic peptide that enhances tumor penetration when conjugated or coadministered with different types of molecules such as drugs, nanoparticles or phages. iRGD-mediated tumor penetration occurs in three steps: binding to αv-integrins on tumor vasculature or tumor cells, exposure by proteolysis of a C-terminal motif that binds to neuropilin-1 (NRP-1) and cell internalization. We have genetically inserted the iRGD peptide in the fiber C terminus of ICOVIR15K, an oncolytic tumor-retargeted adenovirus to increase its tumor penetration. In vitro, NRP-1 interaction improved binding and internalization of the virus in different cancer cells overexpressing integrins and NRP-1. However, such NRP-1-mediated internalization did not affect transduction or cytotoxicity. In vivo, iRGD did not change the normal organ transduction pattern, with liver and spleen as main targeted organs. In tumors, however, iRGD enhanced transduction and early adenovirus dissemination through the tumor mass leading to an improved antitumor efficacy.

Asunto(s)

Terapia Genética/métodos , Oligopéptidos/uso terapéutico , Viroterapia Oncolítica/métodos , Secuencias de Aminoácidos , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Neuropilina-1/metabolismo , Internalización del Virus , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Adenovirus (Ad) i-leader protein is a small protein of unknown function. The C-terminus truncation of the i-leader protein increases Ad release from infected cells and cytotoxicity. In the current study, we use the i-leader truncation to enhance the potency of an oncolytic Ad. In vitro, an i-leader truncated oncolytic Ad is released faster to the supernatant of infected cells, generates larger plaques, and is more cytotoxic in both human and Syrian hamster cell lines. In mice bearing human tumor xenografts, the i-leader truncation enhances oncolytic efficacy. However, in a Syrian hamster pancreatic tumor model, which is immunocompetent and less permissive to human Ad, antitumor efficacy is only observed when the i-leader truncated oncolytic Ad, but not the non-truncated version, is combined with gemcitabine. This synergistic effect observed in the Syrian hamster model was not seen in vitro or in immunodeficient mice bearing the same pancreatic hamster tumors, suggesting a role of the immune system in this synergism. These results highlight the interest of the i-leader C-terminus truncation because it enhances the antitumor potency of an oncolytic Ad and provides synergistic effects with gemcitabine in the presence of an immune competent system.

Asunto(s)

Adenoviridae/genética , Adenoviridae/fisiología , Desoxicitidina/análogos & derivados , Neoplasias/genética , Viroterapia Oncolítica/métodos , Señales de Clasificación de Proteína/genética , Liberación del Virus/fisiología , Adenoviridae/patogenicidad , Animales , Línea Celular Tumoral , Cricetinae , Cartilla de ADN/genética , Desoxicitidina/farmacología , Fluorescencia , Células HEK293 , Humanos , Inmunohistoquímica , Mesocricetus , Ratones , Mutación Missense , Neoplasias/tratamiento farmacológico , Estadísticas no Paramétricas , Liberación del Virus/efectos de los fármacos , Gemcitabina

RESUMEN

Soon after the discovery that viruses cause human disease, started the idea of using viruses to treat cancer. After the initial indiscriminate use, crude preparations of each novel virus in the early twentieth century, a second wave of virotherapy blossomed in the 60s with purified and selected viruses. Responses were rare and short-lived. Immune rejection of the oncolytic viruses was identified as the major problem and virotherapy was abandoned. During the past two decades virotherapy has re-emerged with engineered viruses, with a trend towards using them as tumor-debulking immunostimulatory agents combined with radio or chemotherapy. Currently, oncolytic Reovirus, Herpes, and Vaccinia virus are in late phase clinical trials. Despite the renewed hope, efficacy will require improving systemic tumor targeting, overcoming stroma barriers for virus spread, and selectively stimulating immune responses against tumor antigens but not against the virus. Virotherapy history, viruses, considerations for clinical trials, and hurdles are briefly overviewed (AU)

Asunto(s)

Humanos , Animales , Neoplasias/terapia , Viroterapia Oncolítica , Virus Oncolíticos/fisiología , Neoplasias/inmunología

RESUMEN

Soon after the discovery that viruses cause human disease, started the idea of using viruses to treat cancer. After the initial indiscriminate use, crude preparations of each novel virus in the early twentieth century, a second wave of virotherapy blossomed in the 60s with purified and selected viruses. Responses were rare and short-lived. Immune rejection of the oncolytic viruses was identified as the major problem and virotherapy was abandoned. During the past two decades virotherapy has re-emerged with engineered viruses, with a trend towards using them as tumor-debulking immunostimulatory agents combined with radio or chemotherapy. Currently, oncolytic Reovirus, Herpes, and Vaccinia virus are in late phase clinical trials. Despite the renewed hope, efficacy will require improving systemic tumor targeting, overcoming stroma barriers for virus spread, and selectively stimulating immune responses against tumor antigens but not against the virus. Virotherapy history, viruses, considerations for clinical trials, and hurdles are briefly overviewed.

Asunto(s)

Neoplasias/terapia , Viroterapia Oncolítica , Virus Oncolíticos/fisiología , Animales , Humanos , Neoplasias/inmunología

RESUMEN

Retargeting oncolytic adenoviruses from their systemic preeminent liver tropism to disseminated tumor foci would highly improve the efficacy of these agents at eradicating tumors. We have replaced the KKTK fiber shaft heparan sulfate glycosaminoglycan-binding domain with an RGDK motif in order to achieve simultaneously liver detargeting and tumor targeting. When inserted into a wild-type backbone, this mutation palliated liver transaminase elevation and hematological alterations in mice. Importantly, when tested in a backbone that redirects E1A transcription towards pRB pathway deregulation, RGD at this novel shaft location also improved significantly systemic antitumor therapy compared with the broadly used RGD location at the HI-loop of the fiber knob domain.

Asunto(s)

Adenoviridae/genética , Neoplasias/terapia , Oligopéptidos , Viroterapia Oncolítica/métodos , Animales , Sitios de Unión , Línea Celular Tumoral , Técnicas de Transferencia de Gen , Vectores Genéticos , Heparitina Sulfato/metabolismo , Ratones , Ratones Endogámicos BALB C , Receptores de Superficie Celular/metabolismo

RESUMEN

The limitations of the current oncolytic adenoviruses for cancer therapy include insufficient potency and poor distribution of the virus throughout the tumor mass. To address these problems, we generated an oncolytic adenovirus expressing the hyperfusogenic form of the gibbon-ape leukemia virus (GALV) envelope glycoprotein under the control of the adenovirus major late promoter. The oncolytic properties of the new fusogenic adenovirus, ICOVIR16, were analyzed both in vitro and in vivo, and compared with that of its non-fusogenic counterpart, ICOVIR15. Our results indicate that GALV expression by ICOVIR16 induced extensive syncytia formation and enhanced tumor cell killing in a variety of tumor cell types. When injected intratumorally or intravenously into mice with large pre-established melanoma or pancreatic tumors, ICOVIR16 rapidly reduced tumor burden, and in some cases, resulted in complete eradication of the tumors. Importantly, GALV expression induced tumor cell fusion in vivo and enhanced the spreading of the virus throughout the tumor. Taken together, these results indicate that GALV expression can improve the antitumoral potency of an oncolytic adenovirus and suggest that ICOVIR16 is a promising candidate for clinical evaluation in patients with cancer.

Asunto(s)

Adenoviridae/genética , Vectores Genéticos , Células Gigantes , Virus de la Leucemia del Gibón/genética , Virus Oncolíticos , Adenoviridae/metabolismo , Animales , Línea Celular Tumoral , Cricetinae , Femenino , Regulación Viral de la Expresión Génica , Orden Génico , Terapia Genética , Vectores Genéticos/administración & dosificación , Vectores Genéticos/efectos adversos , Vectores Genéticos/metabolismo , Células Gigantes/virología , Humanos , Inyecciones , Masculino , Ratones , Neoplasias/genética , Neoplasias/patología , Neoplasias/terapia , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs are characterised by the expression of KIT, a type III tyrosine kinase receptor, and the presence of mutations in KIT or PDGFRA in about 80-85% of cases. The primary treatment for GIST is surgery, which cures most patients with low- or intermediate-risk tumours. The introduction of the kinase inhibitor imatinib mesylate, and sunitinib in second line, against KIT and PDGFRA has provided the first evidence of directed therapy in GIST. The aim of this review is to highlight the growing evidence that KIT and PDGFRA genotyping provides valuable information for the clinical management of GIST patients. We show that KIT and PDGFRA genotyping has emerged as one of the principal factors in the evaluation of GISTs, particularly in those tumours that are clearly malignant or have a high risk of recurrence. In addition to helping establish the diagnosis of GIST in unusual cases, genotyping can be very useful to physicians and patients in deciding on imatinib dose, in estimating the likelihood and duration of benefit, and potentially in selecting second-line therapies (AU)

Asunto(s)

Humanos , Masculino , Femenino , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacos , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Antineoplásicos/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Genotipo , Mutación , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico

RESUMEN

Osteosarcoma (OSA) is the most common bone tumor affecting the dog. The veterinary options for therapeutic management of OSA are limited and prognosis for such patients is poor. Oncolytic adenoviruses are attractive tools for experimental therapeutics as they can replicate and spread within tumors to directly induce tumor destruction. However, a major impediment to systemic oncolytic adenoviruses injection is the presence of pre-existing neutralizing antibodies (Nabs). In this study, we investigated the effect of a replication-selective canine adenovirus (OCCAV) to treat OSA in the presence of Nabs and the use of canine OSA cells as carrier vehicles for evading Nabs. Our systemic biodistribution data indicated that canine tumor cells could successfully reach the tumor site and deliver OCCAV to tumor cells in an immunized mice model. Furthermore, the use of carrier cells also reduced adenovirus uptake by the liver. Importantly, OCCAV alone was not effective to control tumor growth in a pre-immunized xenograft mouse model. On the contrary, systemic antitumoral activity of carrier-cell OCCAV was evident even in the presence of circulating antibodies, which is a relevant result from a clinical point of view. These findings are of direct translational relevance for the future design of canine clinical trials.

Asunto(s)

Adenovirus Caninos/metabolismo , Anticuerpos Neutralizantes/metabolismo , Neoplasias Óseas/metabolismo , Virus Oncolíticos/genética , Osteosarcoma/genética , Adenovirus Caninos/genética , Adenovirus Caninos/fisiología , Animales , Antineoplásicos/metabolismo , Línea Celular Tumoral , Perros , Vectores Genéticos/metabolismo , Humanos , Inmunización , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Virus Oncolíticos/metabolismo , Replicación Viral , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of tumours seem to be the cornerstone of any therapy is now emerging. Here we provide an overview on the different approaches to cancer treatment. This review will help the reader to acknowledge the pivotal role of some classic cancer therapies, including surgery, radiation, chemotherapy and endocrine therapy, now better understood in the mechanims underpinning their efficacy. Following, we focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. We briefly elaborate, finally, on new biomarkers development and how it should rule and determine the future of therapeutic research in cancer.

Asunto(s)

Antineoplásicos/uso terapéutico , Neoplasias/terapia , Viroterapia Oncolítica , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Anticuerpos/uso terapéutico , Antineoplásicos/química , Antineoplásicos Hormonales/uso terapéutico , Quimioterapia Adyuvante , Diseño de Fármacos , Humanos , Terapia Neoadyuvante , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/radioterapia , Neoplasias/cirugía , Radioterapia Adyuvante , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento

RESUMEN

Treatment of metastatic tumors with engineered adenoviruses that replicate selectively in tumor cells is a new therapeutic approach in cancer. Systemic administration of these oncolytic adenoviruses lack metastatic targeting ability. The tumor stroma engrafting property of intravenously injected mesenchymal stem cells (MSCs) may allow the use of MSCs as cellular vehicles for targeted delivery. In this work, we study the safety and the efficacy of infusing autologous MSCs infected with ICOVIR-5, a new oncolytic adenovirus, for treating metastatic neuroblastoma. Four children with metastatic neuroblastoma refractory to front-line therapies received several doses of autologous MSCs carrying ICOVIR-5, under an approved preliminary study. The tolerance to the treatment was excellent. A complete clinical response was documented in one case, and the child is in complete remission 3 years after this therapy. We postulate that MSCs can deliver oncolytic adenoviruses to metastatic tumors with very low systemic toxicity and with beneficial antitumor effects.

Asunto(s)

Células Madre Mesenquimatosas/virología , Neuroblastoma/terapia , Viroterapia Oncolítica/métodos , Línea Celular Tumoral , Preescolar , Humanos , Masculino , Neuroblastoma/patología , Neuroblastoma/virología , Virus Oncolíticos/fisiología

RESUMEN

OBJECTIVE: Diabetes mellitus is considered the most common cause of blindness in the working population of industrialized countries, with diabetic macular edema being the most common cause of decreased visual acuity and proliferative diabetic retinopathy (PDR) being responsible for the most severe visual deficits. We have therefore tried to establish a guide for clinical intervention whose purpose is to provide orientation on the treatment of diabetic retinopathy and its complications. This is necessary at a time when many treatment options have emerged whose role is not yet fully defined. METHOD: A group of expert retina specialists selected by the SERV (Vitreous-Retina Spanish Society) assessed the published results of different treatment options currently available, suggesting lines of action according to the degree of diabetic retinopathy present and the presence or absence of macular edema. RESULTS: PDR is primarily treated with pan-retinal photocoagulation. For clinically significant diabetic macular edema without signs of vitreomacular traction, the treatment of choice continues to be focal/grid photocoagulation. Similarly, retinovitreal surgery is indicated for both conditions. The use of antiangiogenic drugs was also analyzed but remains inconclusive. CONCLUSION: Laser therapy is effective in the management of diabetic retinopathy and diabetic macular edema. The role of antiangiogenics is not yet sufficiently defined.

Asunto(s)

Complicaciones de la Diabetes/cirugía , Retinopatía Diabética/cirugía , Fotocoagulación , Edema Macular/cirugía , Vitrectomía , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Bevacizumab , Catarata/etiología , Extracción de Catarata , Complicaciones de la Diabetes/clasificación , Complicaciones de la Diabetes/diagnóstico , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/epidemiología , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/epidemiología , Angiografía con Fluoresceína , Humanos , Inyecciones Intraoculares , Fotocoagulación/métodos , Edema Macular/clasificación , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/epidemiología , Edema Macular/etiología , Hemorragia Retiniana/diagnóstico por imagen , Índice de Severidad de la Enfermedad , Tomografía de Coherencia Óptica , Ultrasonografía , Cuerpo Vítreo

RESUMEN

Objetivo: La diabetes mellitus está considerada como la causa más frecuente de ceguera en lapoblación activa en los países industrializados,siendo el edema macular diabético la causa más frecuentede disminución de la agudeza visual y laretinopatía diabética proliferante la responsable delos déficit visuales más severos. Por ello hemosintentado establecer una guía de actuación clínicacuyo propósito es proporcionar unas directrices quesirvan de orientación para el tratamiento de la retinopatía diabética y sus complicaciones. Esto sehace necesario en un momento en el que han aparecidonumerosas alternativas terapéuticas cuyo papelaún no está completamente definido.Método: Un grupo de expertos retinólogos seleccionadospor la SERV han evaluado los resultadospublicados sobre las distintas opciones terapéuticasque existen en la actualidad, en base a lo cual sesugieren líneas de actuación según el grado de retinopatíadiabética que presenta el paciente y la presenciao no de edema macular.Resultados: El tratamiento princeps de la RDP esla panretinofotocoagulación (PFC). El tratamientode elección en el edema macular diabético clínicamentesignificativo sin signos de tracción vítreomacular continúa siendo la fotocoagulaciónfocal/rejilla. La cirugía retinovítrea tiene así mismosus indicaciones en ambas afecciones. Se discute eluso de fármacos antiangiogénicos.Conclusión: La laserterapia es efectiva en el manejode la RD y del EMD. El papel de los antiangiogénicosaún no está suficientemente definido (AU)

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Objective: Diabetes mellitus is considered the most common cause of blindness in the working populationof industrialized countries, with diabetic macularedema being the most common cause of decreasedvisual acuity and proliferative diabetic retinopathy(PDR) being responsible for the most severevisual deficits. We have therefore tried to establisha guide for clinical intervention whose purpose is toprovide orientation on the treatment of diabetic retinopathyand its complications. This is necessary at a time when many treatment options have emergedwhose role is not yet fully defined.Method: A group of expert retina specialists selectedby the SERV (Vitreous-Retina Spanish Society)assessed the published results of different treatmentoptions currently available, suggesting lines ofaction according to the degree of diabetic retinopathypresent and the presence or absence of macularedema.Results: PDR is primarily treated with pan-retinalphotocoagulation. For clinically significant diabeticmacular edema without signs of vitreomacular traction,the treatment of choice continues to befocal/grid photocoagulation. Similarly, retinovitrealsurgery is indicated for both conditions. The use ofantiangiogenic drugs was also analyzed but remainsinconclusive.Conclusion: Laser therapy is effective in the managementof diabetic retinopathy and diabetic macularedema. The role of antiangiogenics is not yet sufficiently defined (AU)

Asunto(s)

Humanos , Masculino , Femenino , Retinopatía Diabética , Retinopatía Diabética/complicaciones , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/epidemiología , Edema Macular , Tomografía de Coherencia Óptica , Tomografía de Coherencia Óptica/métodos , Fotocoagulación , Vitrectomía , Preparaciones Farmacéuticas , Inhibidores de la Angiogénesis , Inhibidores de la Angiogénesis/uso terapéutico , Diabetes Mellitus , Diabetes Mellitus/terapia

RESUMEN

The E2F-1 promoter has been used to confer tumor-selective E1A expression in oncolytic adenoviruses. Tumor specificity is mainly conferred by a unique structure of E2F-responsive sites organized in palindromes. Binding of the E2F-pRb complex to these palindromes results in repression of transcription in normal cells. Owing to deregulation of the Rb/p16 pathway in tumor cells, binding of free E2F activates transcription and initiates an autoactivation loop involving E1A and E4-6/7. ICOVIR-7 is a new oncolytic adenovirus designed to increase the E2F dependency of E1A gene expression. It incorporates additional palindromes of E2F-responsive sites in an insulated E2F-1 promoter controlling E1A-Delta24. The E2F palindromes inhibited replication in normal cells, resulting in a low systemic toxicity at high doses in immunocompetent mice. The Delta24 deletion avoids a loop of E2F-mediated self-activation in nontumor cells. Importantly, the additional E2F-binding hairpins boost the positive feedback loop on the basis of E1A-mediated transcriptional regulation of E4-6/7 turned on in cancer cells and increased antitumoral potency as shown in murine subcutaneous xenograft models treated by intravenous injection. These results suggest that the unique genetic combination featured in ICOVIR-7 may be promising for treating disseminated neoplasias.

Asunto(s)

Adenoviridae/genética , Proteínas E1A de Adenovirus/biosíntesis , Factor de Transcripción E2F1/genética , Virus Oncolíticos/genética , Regiones Promotoras Genéticas , Animales , Línea Celular , Línea Celular Tumoral , Regulación Viral de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Viroterapia Oncolítica/métodos , Replicación Viral