La inmunoterapia como arma contra el linfoma de Hodgkin

Fuente: http://www.elmundo.es/salud/2014/12/07/5481e511268e3efb708b4595.html

Los linfocitos T del sistema inmunitario (en naranja) se unen a una célula tumoral para destruirla. 

Elegida por la prestigiosa revista Science como el hito médico de 2013, la inmunoterapia continúa conquistando terreno en el campo del tratamiento oncológico. Después de alcanzar importantes logros en el abordaje terapéutico del melanoma y del cáncer de pulmón, ahora, un nuevo trabajo postula que la inmunoterapia también consigue buenos resultados en pacientes con linfoma de Hodgkin, un tumor que se origina en el sistema linfático y que afecta sobre todo a niños y adolescentes, aunque su incidencia es poco frecuente. Un hallazgo que se acaba de presentar en la reunión anual de la Sociedad Americana de Hematología que se está celebrando estos días en San Francisco (California, EEUU).

Con las terapias actuales (quimioterapia, radioterapia), "esta enfermedad puede tratarse con éxito", pero se ha visto que "hasta el 25% de los pacientes finalmente sufre recaída", argumentan los responsables de este estudio, realizado en el Instituto del Cáncer Dana-Farber (Estados Unidos) y publicado en la revista The New England Journal of Medicine.

En este ensayo clínico, Margaret Shipp y Philippe Armand, junto a su equipo de científicos, han querido comprobar los efectos de la inmunoterapia en un grupo de personas que, o bien habían sufrido una recaída o ya no respondían a los tratamientos convencionales.

En total, 23 pacientes han participado en este estudio. Casi el 80% se había sometido a un autotrasplante de células madre (otro posible tratamiento) y más de un tercio había recibido al menos seis líneas previas de tratamiento quimioterápico sin éxito duradero. Es decir, sus casos representaban situaciones en las que no hay más opciones que ofrecer.

Todos ellos recibieron una dosis con nivolumab cada 15 días. Se trata de un anticuerpo que bloquea una proteína denominada PD-1 en la superficie de las células T del sistema inmunológico. Estas células son actores clave en las defensas del organismo. Son las que identifican a las células enfermas o extrañas y luchan contra ellas. Cuando PD-1 se une a otras proteínas llamadas PD-L1 y PD-L2 en la superficie de las células cancerígenas, las células T se paralizan, por lo que el ataque inmunológico contra el cáncer se cancela. Mediante el bloqueo de PD-1, nivolumab permite la actuación del sistema inmunitario. "Este es un tratamiento que, en lugar de atacar a las células cancerígenas, se dirige a la respuesta inmune, la reactivación de las células T", subraya Shipp.

Como explica Mariano Provencio, portavoz de la Sociedad Española de Oncología Médica (SEOM), este fármaco "permite que los linfocitos T del paciente acaben con el tumor. El tumor crea una serie de defensas frente a los linfocitos T (inmunidad) y la inmunoterapia hace frente a estos antígenos tumorales, desarma al tumor". A diferencia de la quimioterapia, agrega el especialista, que también es el presidente del Grupo Oncológico para el Tratamiento y Estudio de los Linformas (GOTEL), "la inmunoterapia es un tratamiento muy selectivo, actúa directamente contra las defensas del tumor".

"Los resultados son especialmente alentadores", coinciden Shipp y Armand. Veinte de los 23 participantes tuvieron una respuesta medible al tratamiento. Cuatro lograron una remisión completa -tumor indetectable-. En el resto, los tumores se redujeron a menos de la mitad de su tamaño original. Seis meses después de finalizar la terapia, el 86% de los pacientes estaban vivos y mantenían su respuesta inmunológica. Al cabo de un año, la mayoría de ellos continuaban bien. "Estamos emocionados por la duración de las respuestas al fármaco", señala Shipp.

Si funciona en este tipo de pacientes, probablemente también "puedan beneficiarse el resto de afectados por este tumor", comenta Provencio. "Los resultados son impresionantes y muy convincentes (aunque aún se trata de una fase I de estudio)". Tal es el éxito de nivolumab que la Agencia Americana del Medicamento (FDA) ha diseñado ya un gran ensayo multinacional en fase II que acaba de ponerse en marcha.

El enfoque de la inmunoterapia encarnado en nivolumab es un legado del trabajo de Gordon Freeman y su esposa, Arlene Sharpe. En los años '80, en la Escuela de Medicina de Harvard, esta pareja inició una investigación que dio lugar a la identificación de las proteínas PD-1 en las células T, así como la PD-L1 y la PD-L2, ligadas a las células tumorales. "Su trabajo fue fundamental para entender que el aumento de la presencia de PD-L1 y PD-L2 en algunas células tumorales pueden permitir que esas células escapen al ataque del sistema inmune", argumenta Shipp.

La alta tasa de respuesta con nivolumab en este estudio puede estar relacionado con las características propias de este tumor. "Hemos visto que las células tumorales del linfoma de Hodgkin con frecuencia tienen una región extra de un cromosoma específico que provoca un aumento de la producción de las proteínas PD-L1 y PD-L2", expone Shipp. "Esta alteración genética característica sugiere que la inhibición de la vía de PD-1 podría ser particularmente eficaz en esta enfermedad".

En cuanto a los efectos adversos, alrededor del 20% sufrió algún tipo de consecuencia grave, aunque "ninguno potencialmente mortal", reza el artículo.

Stem cell transplant without radiation or chemotherapy pre-treatment shows promise

Fuente: http://www.eurekalert.org/pub_releases/2014-12/dci-sct120514.php

Trial reports transplant success in dyskeratosis congenita, a rare bone marrow failure syndrome, following conditioning with immunosuppressive drugs alone.

Suneet Agarwal, M.D., Ph.D., of the Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

Researchers at Dana-Farber/Boston Children's Cancer and Blood Disorders Center report promising outcomes from a clinical trial with patients with a rare form of bone marrow failure who received a hematopoietic stem cell transplant (HSCT) after pre-treatment with immunosuppressive drugs only. This is the first trial reporting successful transplant in dyskeratosis congenita (DC) patients without the use of any radiation or conventional cytotoxic chemotherapy beforehand.

The trial's data were presented by study authors Leslie Lehmann, MD, and Suneet Agarwal, MD, PhD, of Dana-Farber/Boston Children's, at the 56th annual meeting of the American Society of Hematology (abstract #2941). The data suggest that this immunosuppression-only approach could benefit patients with DC--and, perhaps, other bone marrow failure syndromes--who are at high risk of poor transplant outcomes because they cannot tolerate the toxicity of conventional or even reduced-intensity conditioning.

All four participants in the study are alive and well between 10 and 27 months after transplant. None remain dependent on transfusions to maintain blood counts, nor did any experience significant unexpected toxicities or infections during or after transplantation. Were it not for this new regimen, one patient would have been ineligible for transplant due to severe DC-related lung disease.

Conventional transplant conditioning employs radiation and/or high-dose cytotoxic drugs (also known as alkylators) to destroy the bone marrow and blood and immune cells; it also causes widespread cellular damage throughout the body. The process prepares the patient's body to accept the donated stem cells, reducing the risk of rejection and providing a hospitable environment for the new cells to engraft, thrive and produce new blood and immune cells.

In DC and other bone marrow failure syndromes, however, the disease itself already weakens or destroys the patient's bone marrow, raising the question of whether a less toxic approach could effectively condition patients for transplant.

"These data show that it is possible to achieve engraftment within the context of DC using immunosuppression-only conditioning. This experience begs the question of whether we can think more broadly about this approach's applicability for other conditions, something I think is worth considering," Agarwal said.

"Bone marrow failure syndromes are problems of blood and immune cell production," he added. "In theory, then, in some of these conditions it should be possible for healthy donated stem cells to outcompete native cells, without exposing patients to the toxic effects of radiation or alkylating agents."

Eighty percent of patients with DC develop bone marrow failure before reaching age 30. The genetic defects underlying the disease prevent cells from maintaining their telomeres, the caps at the ends of chromosomes that gradually shorten as cells divide and a person ages. As a result, DC patients' hematopoietic stem cells age prematurely and do not divide well. While an HSCT can cure the resulting bone marrow failure, outcomes are often poor, likely because of the toxicity associated with conventional conditioning.

The cellular defects in DC created an opportunity for Agarwal and his collaborators to attempt immunosuppression-only pre-transplant conditioning. Tamping down a patient's immune system, they theorized, would give donor stem cells and their progeny a chance to outcompete the patient's existing cells with a minimal risk of rejection. At the same time, avoiding radiation and alkylators--which cause widespread cellular damage throughout the body--should reduce the risk of long-term HSCT-related complications, such as organ failure and cancer.

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The research was funded by Boston Children's Hospital's Translational Research Program.

The Dana-Farber/Boston Children's Cancer and Blood Disorders Center--the nation's #1 pediatric cancer program, according to US News & World Report 2014-15--brings together two internationally known research and teaching institutions that have provided comprehensive care for pediatric oncology and hematology patients since 1947. The Harvard Medical School affiliates share a clinical staff that delivers inpatient care and surgery at Boston Children's Hospital, most outpatient care at Dana-Farber Cancer Institute.

España, en el primer ensayo mundial sobre el uso de sangre de cordón umbilical para tratar VIH y cáncer hematológico

Fuente: http://noticias.lainformacion.com/salud/enfermedades-viricas/andalucia-en-el-primer-ensayo-mundial-sobre-el-uso-de-sangre-de-cordon-umbilical-para-tratar-vih-y-cancer-hematologico_azPeL2i0i6MCqMrmhQD7a1/

El banco de sangre de cordón umbilical de Málaga realizará tipajes para identificar cordones con la variante genética que elimina el VIH. 

Andalucía participa en el primer ensayo clínico que se realiza a nivel mundial para estudiar la efectividad del uso de la sangre de cordón umbilical en el tratamiento de pacientes con VIH y cáncer hematológico. En concreto, se analizará un tipo de sangre de cordón con una rara mutación genética, conocida como CCR5 Delta 32, que se ha mostrado capaz de eliminar del organismo todo rastro de VIH.

La consejera de Igualdad, Salud y Políticas Sociales, María José Sánchez Rubio, ha subrayado que "la innovación que supone esta nueva indicación del trasplante de células de sangre de cordón umbilical vuelve a situar en la vanguardia a los profesionales del sistema sanitario público".

El Banco de Sangre de Cordón Umbilical de Málaga se encargará, junto al de Barcelona y Madrid, de realizar los tipajes de las unidades de sangre de cordón umbilical para identificar aquéllas en las que se presente la mutación genética analizada en el ensayo clínico. En el proyecto colaboran además los bancos de sangre de cordón umbilical de Canarias, Santiago de Compostela, País Vasco y Valencia.

En todo el país, se realizará el tipaje de 20.000 unidades de sangre de cordón umbilical para identificar los cordones con la variante genética necesaria para este estudio. Se calcula que sólo el uno por ciento de los cordones cumplen estas características. Los cordones además de presentar la mutación genética tienen que poseer una elevada celularidad.

El centro de Málaga realizará el tipaje de más de 9.000 unidades de sangre de cordón umbilical. Actualmente, el banco de cordón de Málaga tiene almacenadas más de 24.000 unidades de sangre de cordón umbilical.

La investigación es impulsada por la Organización Nacional de Trasplantes y se realiza a partir del trabajo realizado por un equipo multidisciplinar del Instituto Catalán de Oncología, en colaboración con el Instituto de Investigación del SIDA IrsiCaixa y el Banco de Sangre y Tejidos de Barcelona, que ha conseguido eliminar la infección por VIH en un paciente VIH con linfoma tratado en 2013.

Hasta ahora, la única intervención médica con evidencia concluyente de curación había sido el caso de un paciente con leucemia aguda mieloide e infección por VIH que recibió en Berlín en 2008 un trasplante de médula ósea de donante no emparentado, cuyas células madre sanguíneas presentaban la variante genética CCR5 Delta 32. Cinco años después del trasplante y de haber suspendido por completo la terapia antirretroviral, el paciente continúa curado de la infección por VIH, lo que a juicio de los expertos, demuestra que esta estrategia ofrece curación a largo plazo.

Positive study data could improve standard of care for Hodgkin lymphoma patients

Fuente: http://medicalxpress.com/news/2014-12-positive-standard-hodgkin-lymphoma-patients.html

In a late-stage clinical trial, Hodgkin lymphoma (HL) patients who received brentuximab vedotin (BV) post-transplant lived longer without disease progression than patients who received only supportive care. This is the first time a study has demonstrated that adding a maintenance therapy after transplant can improve outcomes. The study, led by Craig H. Moskowitz, MD, Clinical Director of the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center, was presented at the 56th Annual Meeting of the American Society of Hematology.

For the past 20 years, high doses of chemotherapy followed by an autologous transplant—a procedure in which a patient's own blood-forming stem cells are collected and then transplanted back into the patient to produce new, healthy blood cells—has been the standard of care for patients with HL who have relapsed or did not respond to initial therapy. This treatment approach typically cures about half of patients. For the other half of patients who remain at risk of disease progression after transplant, there is currently no standard therapy.

"Immense progress has been made to reduce complications for transplant patients," said Dr. Moskowitz. "For most people, a transplant can cure disease. But despite our best efforts, improvements in outcomes have plateaued and new therapies are needed."

BV is an antibody that targets the CD30 protein, which is found on HL cells. A total of 327 patients were randomized to receive either the drug or best supportive care after transplant. All patients had either relapsed or failed to respond to at least one prior therapy but were in remission or had stable, non-progressing disease after salvage chemotherapy prior to transplant.

After a median follow-up of two years, patients who received BV had a 20 percent improvement without disease progression compared to those who did not receive the drug (progression-free survival rate of 65 percent vs. 45 percent); 88 percent of patients who received BV are still alive. Adverse events occurred in less than 15 percent of patients and included peripheral sensory neuropathy, upper respiratory tract infection, neutropenia, and fatigue.

"The results of this trial have the potential to change current practice," said Dr. Moskowitz. "I am excited about the prospect of bringing this new therapy to all patients with hard-to-treat Hodgkin lymphoma."

Técnica de generación de células madre neurales que podría permitir trasplantes de gran envergadura

Fuente: http://noticiasdelaciencia.com/not/12133/tecnica-de-generacion-de-celulas-madre-neurales-que-podria-permitir-trasplantes-de-gran-envergadura/es/

Las células madre neurales inducidas (iNSCs por sus siglas en inglés) creadas a partir de células adultas son prometedoras para el trasplante terapéutico, pero su potencial en esta capacidad se ha visto limitado por los intentos fallidos de mantenerlas en el estado multipotente deseado, sin la expresión continua de los factores de transcripción usados inicialmente para reprogramarlas.

Ahora, unos científicos del Instituto Whitehead de Investigación Biomédica, vinculado al Instituto Tecnológico de Massachusetts (MIT) en Cambridge, Estados Unidos, han creado células madre neurales inducidas que permanecen en el estado multipotente sin una expresión continua de los factores de reprogramación. Esto permite que las células madre neurales inducidas se dividan repetidamente generando así células en cantidad suficiente para posibilitar una terapia basada en ellas.

Terapéuticamente, es importante cultivar células madre neurales porque pueden autorrenovarse y generar muchas células. Si solo se logra obtener neuronas maduras, algo que otras técnicas ya hacen, nunca se puede conseguir una cantidad lo bastante grande de células útiles, y el efecto de cualquier eventual terapia será ínfimo.

A fin de obtener células madre neurales inducidas mediante una conversión directa de linaje, los científicos usan virus que insertan un cóctel de factores de transcripción en el genoma de células adultas de piel (de ratón en los experimentos). Un fármaco pone en marcha a estos factores de transcripción para que activen genes en las células madre neurales. Esta conversión directa, conocida como transdiferenciación, se salta el paso de hacer pasar primero a las células por un estado parecido al de las células madre embrionarias.

La nueva técnica de generación de células madre neurales podría permitir trasplantes de gran envergadura. La ilustración es una recreación artística de nuevas células neurales. 

En investigaciones previas, las células madre neurales inducidas permanecían “adictas” al fármaco y a los factores de transcripción de reprogramación; si cualquiera de ellos era retirado, las células volvían a ser células de piel o se diferenciaban espontáneamente, sin que se las pudiera controlar del modo deseado.

Si los factores de reprogramación siguen aún activos, las células pueden ser incapaces de diferenciarse y las células resultantes difícilmente tendrán la utilidad terapéutica buscada.

El equipo integrado, entre otros, por Rudolf Jaenisch y John Cassady, ha conseguido preservar las propiedades de las células sin mantener activos los factores de reprogramación.

Aunque prometedor, todo el trabajo hasta la fecha ha sido llevado a cabo en células de ratón. Por tanto, primero habrá que probar esta nueva técnica en células humanas para ver si puede producir con éxito las poblaciones celulares necesarias para un uso terapéutico.

En cualquier caso, el paso que se ha dado con esta investigación es un avance importante en el campo, y puede inspirar otros desarrollos futuros.

Información adicional

Las hormonas sexuales femeninas podrían proteger frente a algunas leucemias

Fuente: http://noticiasdelaciencia.com/not/12136/las-hormonas-sexuales-femeninas-protegen-frente-a-algunas-leucemias/es/

El hecho de que los hombres tengan más riesgo de desarrollar leucemia que las mujeres hizo que científicos del Centro Nacional de Investigaciones Cardiovasculares (CNIC) en España comenzaran a investigar la relación entre células madre sanguíneas y hormonas sexuales femeninas.

Los resultados de su trabajo sostienen que dichas hormonas, los estrógenos, son capaces de regular la actividad de las células madre sanguíneas de la médula ósea e influir así en el desarrollo de algunos tipos de leucemia y otros trastornos de la sangre.

Este hallazgo, publicado en la última edición de la revista Cell Stem Cell, puede explotarse en el tratamiento de ciertas leucemias para las que hoy no existen terapias curativas definitivas, las pertenecientes al grupo de las llamadas neoplasias mieloproliferativas.

Los autores, dirigidos por Simón Méndez-Ferrer, del CNIC –en colaboración con los equipos de Jürg Schwaller y Radek Skoda, del Hospital Universitario de Basilea (Suiza)–, han demostrado en ratones que un tratamiento ya aprobado y ampliamente utilizado para el cáncer de mama, el tamoxifeno, bloquea los síntomas y la progresión de dichas neoplasias mieloproliferativas.

Como explica Méndez-Ferrer, “se desconocen las causas de la diferente incidencia de leucemias entre hombres y mujeres, pero las hormonas sexuales, como los estrógenos, podrían explicar al menos parcialmente estas diferencias”.

El investigador aclara que, aunque se sabía que algunos tipos de células sanguíneas estaban regulados por estrógenos, hasta ahora se desconocía su influencia en las células madre sanguíneas, incluyendo aquellas causantes de las neoplasias mieloproliferativas.

A partir de este hallazgo, los científicos descubrieron una importante implicación práctica. “En este trabajo se ha demostrado que el tamoxifeno tiene efectos específicos sobre determinadas células de la médula ósea, en concreto sobre las células madre sanguíneas y su descendencia más inmediata, los llamados progenitores multipotentes”, señala Abel Sánchez-Aguilera, otro de los autores.

En la imagen puede verse al grupo de investigación liderado por Simón Méndez-Ferrer.

La investigación demostró que el tamoxifeno tenía un efecto muy distinto en ratones sanos y enfermos. Así, cuando se administra a ratones normales produce la muerte celular de los progenitores multipotentes, mientras que las células madre aceleran su división y pierden parcialmente su funcionalidad.

En cambio, cuando se administra a animales enfermos, se observa un bloqueo de los síntomas y la progresión de la enfermedad. En definitiva, un efecto terapéutico. A esto se le añade otra ventaja. Sorprendentemente, estos efectos no causan apenas ninguna alteración en el resto de las células sanguíneas, que se mantienen en niveles normales incluso después de tratamientos muy prolongados con el fármaco, no apreciándose ninguna toxicidad.

“El tamoxifeno restaura la muerte celular normal en la célula cancerígena y de esa manera impide que esa célula se acumule y frena específicamente la expansión de las células alteradas. Como lo hace en las células mutantes el efecto neto es una reducción en el número de células leucémicas. Esto no se ha conseguido de manera clara con otros tratamientos en la clínica”, señala Méndez-Ferrer.

Es más, se observó que, a diferencia de lo que ocurre en el cáncer de mama –donde el tamoxifeno bloquea la acción de los estrógenos– en las células sanguíneas el fármaco actúa imitando la función de la hormona.

“Aunque no se conoce exactamente la causa, el tamoxifeno parece tener un efecto más potente sobre las células leucémicas que sobre las sanas, lo que permite bloquear la enfermedad sin causar efectos secundarios importantes sobre las células normales de la sangre”, apunta Méndez-Ferrer.

Uno de los datos más destacados de esta investigación es su potencial traslado a la práctica clínica en un tiempo relativamente corto. “El hecho de que sea un fármaco ya aprobado para uso clínico, y suficientemente seguro, facilita enormemente la posible aplicación de estos resultados para el tratamiento de pacientes con neoplasias mieloproliferativas”, añade.

El científico puntualiza que todavía no se conocen los tiempos para que llegue a la clínica. “El tamoxifeno es un producto genérico en la actualidad y eso dificulta encontrar financiación de farmacéuticas para hacer el ensayo, aunque tenemos contactos con una empresa que estaría potencialmente interesada”, concluye. “Creemos que sería factible diseñar un ensayo clínico pronto”.

Las neoplasias mieloproliferativas, como la policitemia vera –un trastorno de la médula ósea que ocasiona principalmente demasiada producción de glóbulos rojos–, son tumores frecuentemente causados por una mutación en el gen que produce la proteína JAK2 en las células madre sanguíneas, y actualmente no existe para ellas ningún tratamiento curativo, con la excepción del trasplante de médula ósea, solo recomendado en una minoría de pacientes.

La enfermedad provoca la acumulación de células sanguíneas anormales y la degeneración de la médula ósea, procesos que en los animales enfermos son bloqueados por el tamoxifeno. El tratamiento es capaz de eliminar las células madre anormales, responsables últimas de la enfermedad (algo que las terapias actuales, incluyendo los inhibidores de JAK2, no consiguen hacer). 

Studies show immunotherapy drugs improve outcomes in Hodgkin lymphoma patients

Fuente: http://www.eurekalert.org/pub_releases/2014-12/mscc-ssi120514.php

In recent years, a number of scientific breakthroughs have led to the development of drugs that unleash the power of the immune system to recognize and attack cancer. Studies presented at the 56th Annual Meeting of the American Society of Hematology (ASH) highlight the enormous potential these novel treatments have for patients with a variety of hematologic disorders.

For Classical Hodgkin lymphoma (cHL) patients, two phase I studies are already demonstrating dramatic results. A study led by Craig H. Moskowitz, MD, Clinical Director of the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center (MSK), showed that 66 percent of cHL patients had a complete or partial response after receiving the immunotherapy drug pembrolizumab.

"These results are quite extraordinary given the dire circumstances these patients were facing," said Dr. Moskowitz. "Pembrolizumab has already been approved for patients with advanced melanoma and we're excited that the drug is producing responses in other cancer types."

Pembrolizumab is an inhibitor of PD-1, a protein on the surface of T cells that normally regulates the immune system by stopping T cell activation. Some cancers have developed ways of exploiting this shutdown mechanism by interacting with PD-1, enabling the cancer to escape T cell attack. Pembrolizumab blocks PD-1 from stopping T cell activation, allowing the T cells to keep fighting.

MSK physicians played a major role in the clinical trials that led to pembrolizumab's approval and are continuing to conduct trials using the therapy in melanoma, lymphoma, and other cancers.

Dr. Moskowitz's study examined pembrolizumab in 29 patients with cHL who had failed to respond to treatment with brentuximab vedotin. Twenty patients had also relapsed after autologous stem cell transplantation. "Phase I studies are designed for patients who have few, if any, treatment options left," added Dr. Moskowitz.

After twelve weeks, six patients (21 percent) achieved a complete response and thirteen patients (45 percent) went into partial remission. No serious adverse events were reported, and only one patient discontinued therapy because of a moderate side effect.

"Using the immune system as a weapon against cancer is just now beginning to gain momentum," said Dr. Moskowitz. "The results of this study are encouraging as we gather evidence that immunotherapies have the potential to work in many different types of cancer."

A second study presented at the ASH Annual Meeting and simultaneously published in the New England Journal of Medicine showed similarly positive results in cHL patients when using the immunotherapy drug nivolumab, another PD-1 inhibitor.

Twenty-three cHL patients who had failed prior treatment -- 18 of whom had also relapsed after autologous stem cell transplantation -- were given nivolumab. After 24 weeks, four patients (17 percent) achieved a complete response and sixteen patients (70 percent) went into partial remission. Only three serious adverse events were reported.

"These data are the first to be reported for a completed study of a PD-1 inhibitor in Classical Hodgkin lymphoma," said Alexander M. Lesokhin, MD, a medical oncologist at MSK who co-led the study. "This is good news for Hodgkin lymphoma patients and for the advancement of immunotherapies. It's an exciting time to be an oncologist."

Based on these results, the U.S. Food and Drug Administration granted nivolumab Breakthrough Therapy Designation in relapsed cHL. A large phase II trial of this therapy is underway at MSK and other institutions.

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Dr. Moskowitz will present his study on pembrolizumab during an oral presentation at 7:15 AM PST on December 8. Abstract #290: PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study (KEYNOTE-013)

The nivolumab study will be presented during an oral presentation at 7:00 AM PST on December 8. Abstract #289: Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma - Preliminary Safety, Efficacy and Biomarker Results of a Phase I Study

About Memorial Sloan Kettering

We are the world's oldest and largest private cancer center, home to more than 13,000 physicians, scientists, nurses, and staff united by a relentless dedication to conquering cancer. As an independent institution, we combine 130 years of research and clinical leadership with the freedom to provide highly individualized, exceptional care to each patient. And our always-evolving educational programs continue to train new leaders in the field, here and around the world. For more information, go to http://www.mskcc.org.

Study shows more patients with ALS have genetic origin than previously thought

Fuente: http://www.sciencecodex.com/study_shows_more_patients_with_als_have_genetic_origin_than_previously_thought-146901

Genetics may play a larger role in causing Lou Gehrig's disease than previously believed, potentially accounting for more than one-third of all cases, according to one of the most comprehensive genetic studies to date of patients who suffer from the condition also known as amyotrophic lateral sclerosis, or ALS.

The study, conducted by investigators at Cedars-Sinai and Washington University in St. Louis, also showed that patients with defects in two or more ALS-associated genes experience disease onset about 10 years earlier than patients with single-gene mutations.

"These findings shed new light on the genetic origins of ALS, especially in patients who had no prior family history of the disease," said Robert H. Baloh, MD, PhD, director of neuromuscular medicine in the Department of Neurology and director of the ALS Program at Cedars-Sinai. Baloh is senior author of the study, published online in Annals of Neurology.

Typically, researchers classify 90 percent of ALS cases as "sporadic," meaning they occur in patients without a family history of the disease. In their study, however, the researchers found a significant degree of genetic involvement in patients with no family history. Examining DNA from 391 individuals, they identified numerous new or very rare ALS gene mutations in such people. Added to the 10 percent of cases already known to be genetic because of family history, the study suggested that more than one-third of all ALS could be genetic in origin.

Baloh said the presence of the new and rare mutations, found among 17 genes already known to be associated with ALS, does not necessarily mean they all cause the disease. But they are considered likely suspects - especially in combination. ALS often is caused by well-known defects in single genes, but recent studies have suggested that some cases could be brought on by the simultaneous occurrence of two or more "lesser" genetic defects. In theory, each mutation alone might be tolerated without initiating disease, but in combination they exceed the threshold required for disease development.

This study strengthens that possibility: Fifteen patients - nine of whom had no previous family history of ALS - had mutations in two or more ALS-associated genes. The research also takes an important next step, showing that multiple genetic defects can influence the way disease manifests in individual patients. Those with mutations in two or more genes had onset about 10 years earlier than those with defects in only one gene.

Matthew B. Harms, MD, assistant professor of neurology at Washington University and co-corresponding author of the article, said that unknown factors still accounted for the majority of ALS cases.

"This tells us that more research is needed to identify other genes that influence ALS risk, and that ultimately, individuals may have more than one gene contributing toward developing disease," Harms said.

ALS is an incurable, virtually untreatable neurodegenerative disease that attacks motor neurons - nerve cells responsible for muscle function - in the brain and spinal cord. It causes progressive weakness and eventual failure of muscles throughout the body; patients typically survive three to five years after onset.

Investigators in this study used new-generation technology that quickly and efficiently determines the organizational structure of large numbers of genes. They expect this and similar research to usher in personalized medicine in ALS that will allow healthcare teams to analyze a patient's entire genetic makeup and deliver gene-specific therapies to correct detected defects. Cedars-Sinai researchers recently conducted a disease-in-a-dish study with cells from patients with defects in a gene that commonly causes ALS. Using small segments of genetic material to target the defects, they showed that this type of gene therapy can improve neurons from patients with the disease.

These individualized-treatment studies recently received a $1.6-million boost from the ALS Association, which awarded the funds to the Cedars-Sinai Board of Governors Regenerative Medicine Institute as part of an initial distribution of money raised by the ALS Ice Bucket Challenge. With this funding, investigators will employ a specialized stem cell process to create motor neurons from a large number of patients with ALS.

Female sex hormones can protect against the development of some blood disorders

Fuente: http://www.sciencecodex.com/female_sex_hormones_can_protect_against_the_development_of_some_blood_disorders-146831

This discovery has a potential application in the treatment of certain blood disorders for which there is currently no cure. The study was led by Dr. Simón Méndez-Ferrer of the CNIC, working in partnership with the laboratories of Doctors Jürg Schwaller and Radek Skoda of the University Hospital in Basel (Switzerland). The study's authors have demonstrated in mice that tamoxifen, a drug already approved and widely used for the treatment of breast cancer, blocks the symptoms and the progression of a specific group of blood disorders known as myeloproliferative neoplasms.

Dr. Méndez-Ferrer explains that scientists have known for some time that men have a higher risk than women of developing leukemia: "We didn't know the causes off this different incidence of leukemia between men and women, but sex hormones like estrogen could at least partly explain these differences." Although estrogens were known to regulate some types of blood cells, very little was known about their influence on blood stem cells, including those that cause myeloproliferative neoplasms.

From this starting point, the researchers discovered an important practical application. "In this study we demonstrate that tamoxifen has specific effects on certain cells in the bone marrow, the hematopoietic stem cells and their immediate descendants, known as multipotent progenitors," explains study author Abel Sánchez-Aguilera.

This is a graphic of the study. This discovery has a potential application in the treatment of certain blood disorders for which there is currently no cure.

The researchers found that tamoxifen had very distinct effects depending on whether the mice were healthy or sick. When administered to healthy animals, tamoxifen induced cell death of the multipotent progenitors, whereas the stem cells accelerated their division and partially lost their functionality. But when tamoxifen was administered to sick animals, symptoms disappeared and disease progression was blocked. In short, an effective therapy.

And there's another advantage. Surprisingly, these effects cause hardly any discernable alteration in the rest of the blood cells, which are maintained at normal levels even after prolonged treatment with the drug, showing no appreciable toxicity. Unlike the situation in breast cancer, where tamoxifen blocks the action of estrogens, in blood cells the team found that the drug acts by imitating the function of the hormone.

Myeloproliferative neoplasms, like polycythemia vera, are frequent tumors caused by a mutation in the gene that produces the protein JAK2 in hematopoietic stem cells. These diseases currently have no effective cure apart from bone marrow transplant, which is only possible for a small fraction of patients. The disease causes an accumulation of abnormal blood cells and the degeneration of the bone marrow, and in mice both these processes are blocked by treatment with tamoxifen. The treatment is able to eliminate the abnormal stem cells, the root cause of the disease, something that current therapies, including JAK2 inhibitors, don't manage.

This study suggests that the blood stem cells (pink for female, blue for male) that, when altered, produce excessive blood cells (diseases called neoplasms) can be killed by female sex hormones. This finding potentially explains why these diseases and related cancers are more common in men than in women. The approved drug tamoxifen, whose chemical structure resembles female sex hormones and has been used in the picture to depict the feminine symbol (pink), can be used to block the development of blood neoplasms in male and female mice.

Dr. Simón Méndez-Ferrer points out that "although we don't know yet exactly why, tamoxifen appears to have a stronger effect on leukemic cells than on the healthy ones, which allows the disease to be blocked without producing major secondary effects on normal blood cells."

One of the most remarkable features of this study is its potential for translation to clinical practice in a relatively short time. The study's lead author concludes, "The fact that tamoxifen is already approved for clinical use and has an appropriate safety profile enormously increases the chances of these results leading to a clinical trial to test this potential therapy in patients with myeloproliferative neoplasms."

This image shows Simon Mendez - Ferrer's team.

Approved breast cancer drug offers hope for the treatment of blood disorders

Fuente: http://medicalxpress.com/news/2014-12-female-sex-hormones-blood-disorders.html

The discovery has a potential application in the treatment of certain blood disorders for which there is currently no cure. 

Blood cancers are more common in men than in women, but it has not been clear why this is the case. A study published by Cell Press in Cell Stem Cell provides an explanation, revealing that female sex hormones called estrogens regulate the survival, proliferation, and self-renewal of stem cells that give rise to blood cancers. Moreover, findings in mice with blood neoplasms—the excessive production of certain blood cells—suggest that a drug called tamoxifen, which targets estrogen receptors and is approved for the treatment of breast cancer, may also be a valuable strategy for blocking the development of blood neoplasms in humans.

"Our study demonstrates that targeting estrogen signaling with a clinically approved drug, at doses with an acceptable toxicity profile in humans, provides a novel potential therapeutic strategy for a set of neoplasms currently without a definitive cure," said senior study author Simón Méndez-Ferrer of the National Center for Cardiovascular Research (CNIC) in Madrid, Spain.

Myeloproliferative neoplasms cause large numbers of abnormal white blood cells to be produced and enter the bloodstream, potentially causing life-threatening symptoms. These diseases can lead to cancer and arise from blood cells called hematopoietic stem/progenitor cells (HSPCs), which give rise to all of the other blood cells. Leukemia and other blood cancers are more common in men than in women, strongly suggesting that sex hormones such as estrogens contribute to the development of these malignancies. But until now, it has not been clear whether estrogen signaling could directly control normal and cancerous HSPCs.

In the new study, Méndez-Ferrer and Abel Sánchez-Aguilera of CNIC found that HSPCs express estrogen receptors, and activation of these receptors with tamoxifen affected the survival, proliferation, and self-renewal of these cells. In mice with a genetic mutation associated with blood neoplasms, tamoxifen treatment blocked the excessive production of blood cells by restoring normal levels of programmed cell death in mutant cells. Moreover, tamoxifen enhanced the effects of conventional chemotherapy on cancerous cells in a mouse model of leukemia.

The study suggests that the blood stem cells (pink for female, blue for male) that, when altered, produce excessive blood cells (diseases called neoplasms) can be killed by female sex hormones. This finding potentially explains why these diseases and related cancers are more common in men than in women. The approved drug tamoxifen, whose chemical structure resembles female sex hormones and has been used in the picture to depict the feminine symbol (pink), can be used to block the development of blood neoplasms in male and female mice. 

"Our results suggest that tamoxifen, at a similar dose used for the treatment of other diseases, might be useful to treat myeloproliferative neoplasms at various stages, without being toxic to normal blood cells," Méndez-Ferrer says. "The fact that this drug is FDA-approved, readily available and sufficiently safe facilitates the potential translation of our results from the bench to the bedside."

More information: Cell Stem Cell, Sanchez-Aguilera et al.: "Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis" www.cell.com/cell-stem-cell/ab… 1934-5909(14)00514-1