Staphylococcal enterotoxin B as DNA vaccine against breast cancer in a murine model / Enterotoxina B estafilocócica como vacuna de ADN contra el cáncer de mama en un modelo murino

Recently, many efforts have been made to treat cancer using recombinant bacterial toxins and this strategy has been used in clinical trials of various cancers. Therapeutic DNA cancer vaccines are now considered as a promising strategy to activate the immune system against cancer. Cancer vaccines could induce specific and long-lasting immune responses against tumors. This study aimed to evaluate the antitumor potency of the SEB DNA vaccine as a new antitumor candidate against breast tumors in vivo. To determine the effect of the SEB construct on inhibiting tumor cell growth in vivo, the synthetic SEB gene, subsequent codon optimization, and embedding the cleavage sites were sub-cloned to an expression vector. Then, SEB construct, SEB, and PBS were injected into the mice. After being vaccinated, 4T1 cancer cells were injected subcutaneously into the right flank of mice. Then, the cytokine levels of IL-4 and IFN-γ were estimated by the ELISA method to evaluate the antitumor activity. The spleen lymphocyte proliferation, tumor size, and survival time were assessed. The concentration of IFN-γ in the SEB-Vac group showed a significant increase compared to other groups. The production of IL-4 in the group that received the DNA vaccine did not change significantly compared to the control group. The lymphocyte proliferation increased significantly in the mice group that received SEB construct than PBS control group (p < 0.001). While there was a meaningful decrease in tumor size (p < 0.001), a significant increase in tumor tissue necrosis (p < 0.01) and also in survival time of the animal model receiving the recombinant construct was observed.(AU)

Mechanism of action of DSP-7888 (adegramotide/nelatimotide) Emulsion, a peptide-based therapeutic cancer vaccine with the potential to turn up the heat on non-immunoreactive tumors

Background Wilms’ tumor 1 (WT1) is highly expressed in various solid tumors and hematologic malignancies. DSP-7888 (adegramotide/nelatimotide) Emulsion is an investigational therapeutic cancer vaccine comprising three synthetic epitopes derived from WT1. We evaluated the mechanism of action of DSP-7888 Emulsion, which is hypothesized to induce WT1-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs). Methods The ability of nelatimotide and adegramotide to induce WT1-specific CD8+ T cells and CD4+ T cells was assessed in human peripheral blood mononuclear cells (PBMCs). The ability of DSP-7888 Emulsion to induce WT1-specific CTLs in vivo was assessed using human leukocyte antigen-I (HLA-I) transgenic mice. To assess how adegramotide, the helper peptide in DSP-7888 Emulsion, enhances WT1-specific CTLs, HLA-I transgenic mice were administered DSP-7888 or nelatimotide-only Emulsion. Interferon-gamma secretion under antigen stimulation by splenocytes co-cultured with or without tumor cells was then quantified. The effects of combination treatment with DSP-7888 Emulsion and an anti–programmed cell death protein 1 (PD-1) antibody on tumor volume and the frequency of tumor-infiltrating WT1-specific T cells were assessed in HLA-I transgenic mice implanted with WT1 antigen-positive tumors. Result The peptides in DSP-7888 Emulsion were shown to induce WT1-specific CTLs and HTLs in both human PBMCs and HLA-I transgenic mice. Unlike splenocytes from nelatimotide-only Emulsion-treated mice, splenocytes from DSP-7888 Emulsion-treated mice exhibited high levels of interferon-gamma secretion, including when co-cultured with tumor cells (AU)

A new antisarcoma strategy: multisubtype heat shock protein/peptide immunotherapy combined with PD-L1 immunological checkpoint inhibitors

Osteosarcoma, a common malignant tumor in orthopedics, often has a very poor prognosis after lung metastasis. Immunotherapy has not achieved much progress in the treatment because of the characteristics of solid tumors and immune environment of osteosarcoma. The tumor environment is rather essential for sarcoma treatment. Our previous study demonstrated that heat shock proteins could be used as antitumor vaccines by carrying tumor antigen peptides, and we hypothesize that an anti-osteosarcoma effect may be increased with an immune check point inhibitor (PD-L1 inhibitor) as a combination treatment strategy. The present study prepared a multisubtype mixed heat shock protein osteosarcoma vaccine (mHSP/peptide vaccine) and concluded that the mHSP/peptide vaccine was more effective than a single subtype heat shock protein, like Grp94. Therefore, we used the mHSP/peptide vaccine in combination with a PD-L1 inhibitor to treat osteosarcoma, and the deterioration of osteosarcoma was effectively hampered. The mechanism of combined therapy was investigated, and AKT expression participates with sarcoma lung metastasis. This study proposed an antisarcoma strategy via stimulation of the immune system as a further alternative approach for sarcoma treatment and elucidated the mechanism of combined therapy (AU)

Inmunotherapy in prostate cancer / Inmunoterapia en cáncer de próstata

Prostate cancer (PCa) is the second most commonly diagnosed cancer. Although systemic chemotherapeutic agents, such as cabazitaxel, abiraterone and enzalutamde have become available to patients over the last decade, metastatic PCa is still an incurable disease. Immunotherapy is showing great promise in a wide range of other cancer types. To this day, the only immunotherapy approved by the FDA for PCa is the Sipuleucel-T vaccine, which showed significant clinical efficacy. Multiple clinical studies on immunotherapy in PCa are currently underway. Objectives: Recent clinical trials have shown promising results in immunotherapeutic in treatment for PCa. The authors review previous clinical trials, as well as discuss and emphasize important emerging immunotherapies for PCa. Methods: Review of the published evidence related to immunotherapy in PCa. PubMed and clinicaltrials.gov databases were used to search for English papers and clinical trials. Results: Multiple clinical trials are testing different immunotherapeutic agents, as well as combinations thereof. The low grade of toxicity associated with these immunotherapies is an appealing advantage for patients, leading to an increased appreciation of theses types of treatments. Until now, only one clinical trial led to a new immunotherapeutic agent to be FDA approved. Important phase II/III clinical trials are being conducted, and in the near future the concept of PCa treatment might be re-challenged. Conclusions: Many trials are ongoing to determine the effects of immunotherapy in PCa. These studies may harvest important confirmatory data in the next years, with the potential to reshape PCa treatment

El cáncer de próstata (CaP) es el segundo cáncer más frecuente. Aunque durante la última década se han hecho disponibles agentes quimioterápicos como Cabazitaxel, Abiraterona y Enzalutamida, el CaP metastásico es todavía una enfermedad incurable. La inmunoterapia está mostrándose muy prometedora en un amplio rango de cánceres de otro tipo. Hasta la fecha, la única inmunoterapia aprobada por la FDA para el CaP es la vacuna Sipuleucel-T, que demostró eficacia clínica significativa. Actualmente, hay múltiples ensayos clínicos de inmunoterapia en CaP en marcha. Objetivos: Ensayos clínicos recientes han mostrado resultados prometedores de la inmunoterapia en CaP. Los autores revisan los ensayos clínicos previos y también discuten y enfatizan importantes tratamientos inmunoterapéuticos emergentes en CaP. MÉTODOS: Revisión de la evidencia publicada relacionada con inmunoterapia en CaP. Se utilizaron las bases de datos PubMed y clinicaltrials.gov para buscar artículos en inglés y ensayos clínicos. Resultados: Múltiples ensayos clínicos están evaluando diferentes agentes inmunoterapicos, así como combinaciones. El bajo grado de toxicidad asociado con estas inmunoterapias es una ventaja atractiva para los pacientes, que conduce a un aumento de la valoración de este tipo de tratamientos. Hasta ahora, solamente un ensayo clínico ha llevado a la aprobación por la FDA de un nuevo agente inmunoterapico. Se están llevando a cabo importantes ensayos clínicos fase II/III, y en un futuro próximo el concepto de tratamiento del CaP podría ser desafiado de nuevo. Conclusiones: Están en marcha muchos ensayos clínicos para determinar los efectos de la inmunoterapia en CaP. Estos estudios pueden obtener importantes datos confirmatorios en los próximos años, con el potencial de redefinir el tratamiento del CaP

Inmunoterapia en cáncer de próstata resistente a la castración / Immunotherapy in castration resistant prostate cancer

Revisamos el papel de la inmunoterapia en el cáncer de próstata resistente a castración. Se han aplicado dos estrategias inmunoterápicas, de forma aislada o en combinación, bien entre ellas o bien con otros agentes de eficacia demostrada en este escenario y que ejercerían un papel inmunomodulador: vacunas o anticuerpos monoclonales destinados al bloqueo de puntos de control inhibidores de la respuesta inmune. Aunque a priori el CPRC presenta características que sugieren que la inmunoterapia podría jugar un papel relevante como estrategia terapéutica, su aplicación clínica ha demostrado una actividad limitada y heterogénea, en cuanto a la proporción de respondedores e intensidad de respuesta. En términos generales, la tasa de respuestas objetivas es muy baja, aunque, en los pacientes que responden, es posible detectar un beneficio claro y duradero. Sólo la vacuna autóloga Sipuleucel T ha demostrado un aumento de la supervivencia global en pacientes con criterios de buen pronóstico. Es característico en estos tratamientos que no se observe un incremento en la supervivencia libre de progresión debido a su propio mecanismo de acción. Tampoco la evolución del PSA puede considerarse una variante subrogada de respuesta radiológica o beneficio clínico en este entorno. Se hace necesario identificar qué características de los pacientes o del tumor son capaces de maximizar la respuesta. Una limitación importante es la ausencia de biomarcadores predictores de respuesta que sirvan para la preselección de pacientes. Como norma general, las mejores respuestas con tratamientos inmunoterápicos aislados se han observado en pacientes con baja carga tumoral, lo cual puede sugerir que su aplicación óptima podría ser en fases más precoces de la enfermedad (localizado de alto riesgo, fracaso bioquímico, etc.). La estrategia de combinación, sin lugar a dudas la de más futuro, se fundamenta en que los tratamientos adicionales incrementan la lisis celular con la consiguiente exposición antigénica y/o ejercen un efecto inmunomodulador capaz de vencer la tolerancia inmunológica inducida por el tumor. Los resultados obtenidos sugieren que la inmunoterapia puede ser más efectiva en modo tratamiento combinado con otros tratamientos activos (abiraterona, enzalutamida, Radio 223, docetaxel) en la lucha por lograr cronificar la enfermedad

We review the role of immunotherapy in castration resistant prostate cancer. Two immunotherapeutic strategies have been applied, isolated or in combination, either with each other or with other agents with demonstrated efficacy in this scenario that would play a role as immunomodulators: vaccines or monoclonal antibodies aimed to block immune response checkpoint inhibitors. Although CRPC presents, a priori, characteristics suggesting that immunotherapy may play a relevant role as a therapeutic strategy, its clinical application has demonstrated a limited and heterogeneous activity, in terms of proportion of responders and response intensity. Generally, the objective response rate is very low, although, in patients who have response it is possible to detect a clear, long-lasting benefit. Only the autologous vaccine Sipuleucel T has demonstrated an overall survival increase in patients with good prognosis criteria. In these treatments, it is characteristic that no progression free survival increase is visible due to its action mechanism. PSA evolution may not be considered a surrogate variable of radiological response or clinical benefit in this environment either. It is necessary to identify what patient`s or tumor's characteristics are able to maximize the response. An important limitation is the absence of response predictive biomarkers that serve for patient preselection. As a general rule, the best responses with isolated immunotherapeutic treatments have been observed in patients with low tumor load, which may suggest that their optimal application could be in earlier phases of the disease (high risk localized, biochemical failure, etc) Combination strategy, without doubt the one with best future, is based on additional treatments increasing cell lysis with the subsequent antigen exposure and/ or producing an immunomodulatory effect that can surmount tumor induced immunologic tolerance. The results obtained suggest that immunotherapy may be more effective in combined therapy with other active therapies (abiraterone, enzalutamide, Radium 223, docetaxel) in a fight to achieve disease chronification

Gynecological management of patients diagnosed with fanconi anemia / Manejo ginecológico de la paciente diagnosticada de anemia de fanconi

We present the gynecological and clinical management of women diagnosed with Fanconi anemia at our hospital, which is a reference center in Spain. Fanconi anemia is considered a rare disease. It is an autosomal recessive chromosomal instability syndrome in which more than 20 genes are affected. The disease involves progressive bone marrow failure, various congenital abnormalities, and an increased predisposition to cancer; hence the importance of a gynecological management protocol

Presentamos el manejo clínico ginecológico que llevamos a cabo en nuestro hospital de las pacientes mujeres diagnosticadas con anemia de Fanconi; siendo nuestro hospital uno de los hospitales de referencia en nuestro país. La anemia de Fanconi, considerada como una de las enfermedades raras, es una enfermedad autosómica recesiva, con inestabilidad cromosómica. En la actualidad se han descrito más de 20 genes afectados. Clínicamente hay una insuficiencia medular progresiva, diversas anomalías congénitas e incremento a la predisposición a producir cáncer; de allí la importancia de protocolizar la actuación de manejo de estas pacientes desde el punto de vista ginecológico

Influence of ovarian cancer type I and type II microenvironment on the phenotype and function of monocyte-derived dendritic cells

PURPOSE. The aim of this study was to evaluate the influence of ovarian cancer cell lysates isolated from type I or type II ovarian cancer (OC) on the phenotype of monocyte-derived dendritic cells (Mo-DCs) and the cytokine profile. We also determined whether the Mo-DCs and tumor microenvironment, reflected by peritoneal fluid (PF) from type I or II ovarian cancer, could promote regulatory T cell (Tregs) differentiation from naive CD4+ lymphocytes in vitro. RESULTS. Our results show a significant role of the ovarian cancer microenvironment reflected by PF from type I or II OC in the inhibition of the DC differentiation process. Interestingly, the percentage of cells co-expressing CD45 and CD14 antigens in the cultures stimulated with PF from both type I and type II OC was higher than in the control. Furthermore, the percentage of cells expressing CD1a, i.e., a marker of immature DCs, was significantly reduced in the cultures stimulated with PF from type I and type II OC. The results obtained show that ovarian cancer type II lysates induce differentiation of monocytes into macrophage-like cells with a CD1a+/HLA-DR+/CD83− phenotype and significantly higher CD86/HLA-DR expression. We show that ovarian cancer type II Mo-DCs are able to prevent an immune response by release of IL-10, whereas OC type I Mo-DCs can promote the generation of Tregs. CONCLUSIONS. We demonstrate that each type of ovarian cancer can induce a unique phenotype of DCs and differentiation of Tregs, both associated with immune-suppressive function, which may be an obstacle while developing effective anticancer dendritic cell vaccination (AU)

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Potenciación de la actividad antitumoral de doxorrubicina mediante su formulación en nanoplataformas magnéticas / Improvement of the antitumor activity of doxorubicin by the use of magnetic nanoplatforms

El diseño de sistemas transportadores basados en nanopartículas magnéticas pretende la acumulación en el tejido tumoral de la dosis de fármaco administrada. Así debe obtenerse una mejora significativa del efecto anticanceroso, junto con la minimización de la toxicidad asociada. En este contexto, desarrollamos una metodología reproducible de formulación de nanopartículas constituidas por núcleos de óxido de hierro (magnetita) embebidos en una matriz de poli (E- caprolactona). La extensa caracterización fisicoquímica de estos nanocompuestos permitió definir las condiciones óptimas de formulación para asegurar el transporte eficaz de fármacos. Se estudió la capacidad de la nanoplataforma para desarrollar un efecto antitumoral de hipertermia, su compatibilidad sanguínea y su utilización por vía intravenosa como sistema transportador de doxorrubicina hasta el tejido canceroso. Las nanopartículas magnetita/pol i(E-caprolactona) presentaron una adecuada vehiculización de este fármaco, junto con una muy significativa susceptibilidad magnética. Finalmente, se analizó la actividad antitumoral de los nanocompuestos cargados con doxorrubicina en un modelo de tumor subcutáneo EMT6 inducido en ratones. Se observó que éstos presentaban un marcado efecto quimioterápico en comparación con tratamientos alternativos (p.ej., la administración de estas nanopartículas sin guiado magnético hasta la masa tumoral, o el tratamiento con una solución intravenosa de doxorrubicina). Los resultados obtenidos resaltan las interesantes propiedades que presenta la nanoformulación diseñada para el desarrollo de una terapia eficaz contra el cáncer(AU)

The introduction of magnetic nanoplatforms in the cancer arena is intended to optimize the accumulation of the drug dose into the tumor interstitium with the help of a magnetic gradient. As a result, the chemotherapeutic agent may exhibit an enhanced anticancer efficacy and a negligible systemic toxicity. In these contexts, we have developed a reproducible methodology for the design of magnetite/poly (E-caprolactone) core/shell nanoparticles. A detailed physicochemical characterization of these nanocomposites suggested that their heterogeneous structure allows their use in drug delivery, thanks to an excellent responsiveness to magnetic gradients. In vitro heating characteristics (hyperthermia inducing capability) of the core/shell nanoparticles were investigated in a high frequency alternating magnetic gradient. Blood compatibility of the nanoformulation was defined in vitro. Finally, this nanodevice was used to enhance the intravenous delivery of the anticancer agent doxorubicin to the tumor tissue. The nanocomposites were characterized by an adequate doxorubicin loading, a significant magnetic susceptibility, and a low burst drug release. When injected to the EMT6 subcutaneous mice tumor model, these doxorubicin-loaded core/shell nanoparticles were magnetically guided, and they displayed considerably greater anticancer activity than the other anticancer treatments (i.e., doxorubicin-loaded nanocomposites non-magnetically guided, or doxorubicin free in solution). Thus, the here-described stimuli-sensitive nanomedicine possesses important characteristics for effective therapy of cancer(AU)

Lack of T-cell responses following autologous tumour lysate pulsed dendritic cell vaccination, in patients with relapsed osteosarcoma

BACKGROUND: Immunotherapy using autologous dendritic cell (DC) vaccination has not been systematically evaluated in osteosarcoma. We therefore conducted a phase I trial to assess feasibility, safety and tumour-specific immune responses in patients with relapsed disease. PATIENTS AND METHODS: Of 13 recruited patients with relapsed osteosarcoma, 12 received 3 weekly vaccines of autologous DCs matured with autologous tumour lysate and keyhole limpet haemocyanin (KLH), to a maximum of 6 vaccinations. An additional 3 paediatric patients afflicted with other tumour types and with relapsed disease received vaccines generated with identical methodology. Immune responses were assessed using an ELISpot assay for the detection of interferon gamma, whilst interleukin-2 and granzyme B were additionally assessed in cases where interferon-γ responses were induced. RESULTS: In total 61 vaccines, of homogeneous maturation phenotype and viability, were administered with no significant toxicity. Only in 2 out of 12 treated osteosarcoma cases was there an induction of specific T-cell immune response to the tumour, whilst a strong but non-specific immune response was induced in 1 further osteosarcoma patient. Immune response against KLH was induced in only 3 out of 12 osteosarcoma patients. In contrast, three additional non-osteosarcoma patients showed significant T-cell responses to vaccine. CONCLUSION: We have shown the strategy of DC vaccination in relapsed osteosarcoma is safe and feasible. However, significant anti-tumour responses were induced in only 2 out of 12 vaccinated patients with no evidence of clinical benefit. Comparison of results with identically treated control patients suggests that osteosarcoma patients might be relatively insensitive to DC-based vaccine treatments (AU)

Vacuna idiotípica en el tratamiento del linfoma folicular: situación actual y perspectivas futuras / Idiotype vaccines in the treatment of follicular lymphoma: current status and future perspectives

El linfoma folicular (LF) está considerado como elsegundo tipo de linfoma no-Hodgkin más común, representandomás del 20% del total de los linfomas. Es unaenfermedad de progresión lenta y curso indolente enla que, a pesar de la buena respuesta al tratamiento,las recaídas son muy frecuentes y cada vez es más difícilconseguir respuestas completas. Por ello, se puedeconsiderar que hasta el momento, el LF es incurable.La búsqueda continua de nuevas estrategias terapéuticasen enfermedades neoplásicas, junto con un mejorconocimiento del sistema inmunitario, ha llevado ala aparición de una nueva disciplina, conocida con elnombre de inmunoterapia, que aprovecha la capacidaddel sistema inmunitario de atacar lo extraño sin dañarlo propio. El LF es un tumor muy apropiado para estetipo de tratamiento por presentar un antígeno específicode tumor: el idiotipo de la inmunoglobulina monoclonalexpresada en la membrana de todas las célulastumorales. Se han realizado diversos estudios en losque se ha probado la inmunoterapia como tratamientocomplementario al tratamiento convencional. Recientemente,nuestro grupo ha publicado un estudio en el quese observa claramente que los resultados que se obtienentras la vacunación idiotípica, cuando se consigue lainmunización adecuada del paciente, son mejores quelos obtenidos con quimioterapia sola. En este sentido,es necesario seguir investigando para aclarar si la vacunaciónidiotípica pudiera no sólo mantener remisionescompletas duraderas en los pacientes vacunados, sinoincluso conseguir la curación de los mismos. Por ello,resulta interesante abordar un mejor planteamiento delos ensayos clínicos, la mejora de la producción de lavacuna y el estudio de mecanismos de la célula tumoralcapaces de modificar la inmunoglobulina específica del tumor(AU)

Follicular lymphoma is the second most prevalentnon-Hodgkin lymphoma, representing 20% of all lymphomas.Follicular lymphoma is an indolent diseasewith a slow progression in which, although exhibitinga good response to treatment, relapse is very frequentand complete remission is not easy to maintain. Therefore,the disease is regarded as incurable. The searchfor new therapeutic strategies, together with a betterunderstanding of the immune system, has led to theemergence of a new treatment named immunotherapy.Follicular lymphoma is a malignancy suitable for thiskind of treatment given the fact that it is characterizedby presenting a unique tumour-specific antigen: theidiotype of the monoclonal immunoglobulin displayedon the membrane of tumour cells. Several studies havebeen conducted to test immunotherapy as complementaryto conventional treatment. In a previous study byour group, a clear benefit was evident is obtained afteridiotypic vaccination, when an adequate immunizationof the patient is obtained, in comparison to chemotherapyalone. In this sense, analysis is needed of whetheridiotypic vaccination can produce not only long-lastingand complete remission, but even cure. It would be ofgreat interest to consider an optimisation of the experimentaldesign of clinical trials, an improvementof vaccine production, and the study of the molecularmechanisms of the tumour cell which modify the targetimmunoglobulin(AU)

Therapeutic vaccines for non-Hodgkin B-cell lymphoma

Despite current therapeutic strategies for B-cell lymphoma, including chemotherapy and transplantation, the majority of patients are not cured. The characterisation of several tumour antigens has made immunotherapy an interesting approach to the treatment of patients with lymphoma. The idiotype region in the immunoglobulin expressed by the tumour B cells is not only a clonal marker but also a tumour-specific antigen. For this reason, the idiotype is an ideal target for immunotherapy. Extensive studies of idiotype vaccination have been done in murine lymphoma models and some of these strategies are now being tested in clinical trials. In the last few years, new strategies to improve the immune response against lymphoma cells have been studied, including the use of DNA or recombinant viruses encoding tumour-antigens, genetically modified tumour cells and a number of immune adjuvants targeting dendritic cells, T cells or NK cells (AU)

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Inmunoterapia activa en cáncer de próstata: revisión con atención especial a las células dendríticas / Active immunotherapy of prostate cancer with a focus on dendritic cells

El cáncer de próstata recurrente o metastásico generalmente se considera incurable. Dado que el beneficio del tratamiento de deprivación hormonal es transitorio y los éxitos de la quimioterapia sistémica limitados, son necesarias modalidades alternativas de tratamiento, tanto para la recurrencia de PSA como para la enfermedad hormono-refractaria. Las células cancerígenas prostáticas expresan varios antígenos asociados a tumores que están siendo evaluados actualmente como dianas para abordajes de inmunoterapia activa y específica. Las células dendríticas son las células presentadoras de antígenos más potentes, capaces de activar las células T vírgenes y romper la tolerancia periférica, y así inducir respuestas inmunes a tumores. Hasta la fecha, cerca de 1.000 pacientes con cáncer de próstata han sido tratados con inmunoterapia activa, basada en células dendríticas o de otro tipo. Se han comunicado respuestas inmunes inducidas por la vacunación en dos tercios de los ensayos clínicos con células dendríticas, y cambios favorables de la evolución clínica de la enfermedad en casi la mitad de los pacientes tratados. Sin embargo, la mayoría de las respuestas fueron modestas y transitorias. Por lo tanto, los mecanismos de fallo del tratamiento y las posibilidades de mejoría de la eficacia de la vacunación están siendo discutidos

Recurrent or metastatic prostate cancer is generally considered an incurable disease. Given the transient benefit from hormone deprivation therapy and limited successes of systemic chemotherapy, alternative treatment modalities are needed both in the situation of PSA recurrence and in hormonerefractory disease. Prostate cancer cells express several tumor associated antigens which are currently being evaluated as targets for active and specific immunotherapy approaches. Dendritic cells (DC) are the most powerful antigen-presenting cells (APC), able to prime naïve T cells and to break peripheral tolerance and thus induce tumor immune responses. Close to 1000 prostate cancer patients have been treated with DC-based or other forms of active immunotherapy to date. Vaccination-induced immune responses have been reported in two thirds of DC trials, and favorable changes in the clinical course of the disease in almost half of the patients treated. Most responses, however, were modest and transient. Therefore, mechanisms of treatment failure and possibilities to improve vaccination efficacy are being discussed

Novedades en el tratamiento del cáncer de próstata metastático hormono-independiente / Novel promising treatment options for metastatic androgen independent prostate cancer

Objetivo: revisar los últimos avances en el tratamiento del cáncer de próstata hormono-independiente (CPHI). Metodología: revisión de los últimos resúmenes de comunicaciones y presentaciones en congresos, y de la literatura científica utilizando las siguientes palabras clave para búsquedas en Medline/PubMed: androgen independent/hormone refractory prostate cancer, novel treatment options. Revisión de ensayos clínicos en fase II y fase III. Conclusión: dos estudios de gran trascendencia, -el SWOG 9916 y el Taxotere 327- han probado que la supervivencia de los pacientes con CPHI puede mejorar tras la administración intravenosa de docetaxel cada 3 semanas. La combinación de docetaxel y prednisona proporciona supervivencias de 19 meses, mientras que la asociación de mitoxantrona y prednisona se sigue de supervivencias de 16 meses. A pesar de esa diferencia, todavía es necesario mejorar el beneficio en términos de supervivencia, dado que el período libre de recidiva entre los respondedores es frecuentemente breve (6 meses), y los pacientes a menudo mueren por progresión tumoral. El satraplatino (un nuevo análogo del platino) utilizado en segunda línea ha proporcionado un beneficio adicional de 1,5 semanas libres de progresión. No obstante, es necesario desarrollar drogas menos tóxicas para mejorar significativamente la supervivencia

Objective: Review the recent advances in the treatment of androgen independent prostate cancer (AIPC). Methods: Review recent abstracts and literature utilizing Medline/PubMed using key words: androgen independent/ hormone refractory prostate cancer, novel treatment options, Phase II, III trials and meeting abstracts/ presentations. Conclusion: Two pivotal trials SWOG (Southwest Oncology Group) study 9916 and Taxotere 327 have shown that survival can be improved in this population by administration of chemotherapy with docetaxel every three weeks intravenously. An overall survival of 19 months could be achieved with docetaxel/prednisone compared to16 months with mitoxantrone/prednisone. Despite this, there is a need to improve on this survival benefit because the relapse free survival among responders is often short (6 months) and patients often would have progression of their cancer leading to death. Satraplatin, a novel platinum analogue had been found to provide an additional 1.5 week progression free survival benefit in this population in the second line setting. There is however, a need to develop less toxic drugs that would improve survival significantly

El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas / The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases

La manipulación farmacológica del sistema inmunitario para conseguir respuestas linfocitarias de mayor intensidad tiene aplicación potencial en inmunoterapia tumoral y en el tratamiento de enfermedades virales crónicas. Los anticuerpos monoclonales inmunoestimuladores se definen como una familia de fármacos que aumentan la respuesta inmunitaria al interaccionar como ligandos artificiales con proteínas funcionales del sistema inmunitario, activando o inhibiendo su función. Hay anticuerpos monoclonales humanizados dirigidos frente al receptor inhibidor linfocitario CD152 (CTLA-4) que se están probando en ensayos clínicos con evidencia de actividad antitumoral, aunque con la contrapartida de producir reacciones autoinmunitarias severas. Los anticuerpos anti-CD137 tienen la capacidad de inducir potentes respuestas inmunitarias, mediadas principalmente por linfocitos T citotóxicos, con el resultado de erradicar tumores transplantables de ratón de forma comparativamente superior a los anticuerpos frente a CD152. CD137 (4-1BB) es un antígeno de diferenciación expresado selectivamente en la superficie de linfocitos T y NK activados y sobre células dendríticas. Los anticuerpos monoclonales que actúan como ligandos artificiales estimuladores de este receptor (anticuerpos monoclonales agonistas anti-CD137) potencian la inmunidad celular antitumoral y antiviral en modelos experimentales murinos. Paradójicamente, estos mismos anticuerpos previenen o mejoran el curso de enfermedades autoinmunitarias establecidas en ratones como modelo. A la luz de estos datos experimentales, varios grupos de investigación han procedido a la humanización de anticuerpos dirigidos frente a CD137 humano y se plantea la inminente realización de los primeros ensayos clínicos

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start

Vacunas en melanoma / Melanoma vaccines

Las vacunas terapéuticas han demostrado ser una de las mejores estrategias de intervención en el sistema inmune para proteger al organismo en contra de la progresión de una amplia variedad de enfermedades, incluyendo el cáncer. En este trabajo ofrecemos una revisión de las principales modalidades de vacunas terapéuticas que se han ensayado clínicamente y han demostrado algún efecto antitumoral. Aunque en la actualidad se están desarrollando varios ensayos clínicos fase III con resultados alentadores, la terapia con vacunas de melanoma es todavía experimental y su efectividad no esta demostrada (AU)

Un nuevo concepto: inmunizaciones terapéuticas / A new concept: therapeutic immunisation

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La célula dendrítica: biología y aplicaciones en inmunoterapia / The dendritic cell: biology and applications in immunology

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Vacunas antitumorales en desarrollo clínico / Clinical development of antitumoral vaccines under

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Vacunas para el cáncer de próstata. ¿Misterio o realidad? / Vaccinations for prostate cancer. Mystery or reality?

Las limitaciones de los abordajes terapéuticos actuales hacen al cáncer de próstata un claro objetivo de la inmunoterapia, mediante el uso de vacunas contra este tumor. Las estrategias inmunoterapéuticas incluyen modificaciones genéticas ex vivo e in vivo, o la inmunomodulación. El principio de los estudios ex vivo es manipular genéticamente las células tumorales in vitro, para producir una vacuna terapéutica inmunogénica con el objetivo de producir una vacuna terapéutica inmunogénica con el objetivo de estimular la respuesta inmune del huésped. Las estrategias in vivo intentan producir una respuesta inmune contra el tumor del huésped mediante el cruce con varios antígenos, por ejemplo, células enteras, o células dendríticas pulsadas con antígenos o péptidos antigénicos. Esta revisión discute las interacciones entre células tumorales y células presentadoras de antígenos, así como las que ocurren entre células T, y la lógica tras la aplicación clínica de vacunas celulares autólogas y alogénicas. (AU)