First patient treated in OneChain Immunotherapeutics’ CAR-T trial for cortical T-cell acute lymphoblastic leukemia

  • OneChain Immunotherapeutics announces the treatment of the first patient in the CARxALL clinical trial evaluating its most advanced product, OC-1. The trial, conducted in Barcelona at Hospital Clínic and Hospital Sant Joan de Déu, is open to both pediatric and adult patients worldwide.
  • OneChain Immunotherapeutics is a spin-off of the Josep Carreras Leukaemia Research Institute and ICREA, in partnership with Invivo Ventures, CDTI-Innvierte and the Josep Carreras Leukaemia Foundation.
  • Cortical T-cell acute lymphoblastic leukemia accounts for 20-30% of T-cell leukemias and has a poor prognosis in patients who do not respond to standard treatments.
  • OC -1 is a CAR-T cell therapy targeting antigen CD1a, a protein almost exclusively present on tumor cells, potentially reducing severe immunosuppression risks associated with competing CAR T treatments. It has received orphan drug designation by both EMA and the FDA.

OneChain Immunotherapeutics (OCI), a biotechnology company specializing in the development of CAR-T cell therapies for oncological diseases, announced today the first patient dosed in the CARxALL clinical trial, a study evaluating its most advanced product, OC-1, in patients with cortical T-cell acute lymphoblastic leukemia (coT-ALL). The trial, open to pediatric and adult patients worldwide, is being conducted in Barcelona at Hospital Clínic and Hospital Sant Joan de Déu, under the direction of Dr Núria Martínez and Dr Susana Rives, principal investigators for the study.

The CARxALL study (ClinicalTrials.gov identifier NCT05679895), is a dose-escalation trial, aiming to evaluate for the first time in humans the safety and tolerability of a CAR-T therapy (OC-1) in patients with coT-ALL, a subtype of leukemia that accounts for 20% of T-cell leukemias and is characterized by a poor prognosis in those patients who do not respond to existing therapies. The first patient treated at Hospital Clínic, a young man who had previously undergone several treatment lines without success, has received the full dose with no major issue.

«This treatment offers hope for patients who have exhausted all available options», explains Núria Martínez, Principal Investigator at Hospital Clínic. «It is essential that we do everything we can to ensure that as many patients as possible can access these innovative therapies. We are very grateful to OneChain for all their support with the clinical trial and hope to stablish a long-lasting relation with them. Their pipeline has a lot to offer to patients and families».

CAR-T therapies are a type of immunotherapy that involves the genetic modification of immune cells called T-cells in the laboratory, to enhance and target their ability to recognize and attack cancer cells. This strategy has already shown promising results in other forms of leukemia and lymphoma. However, applying these therapies to T-cell leukemias such as coT-ALL presents significant challenges because tumor and healthy T cells exhibit almost the same molecules on their surface. As a result, competing CAR T therapies aimed at T-ALL destroy both type of cells, potentially leading to severe immunosuppression in patients.

OC-1, the product being evaluated in the trial, aims to overcome these obstacles by targeting CD1a, a specific protein found almost exclusively in the tumor cells of patients with coT-ALL. «Our laboratory was the first to develop and validate a CAR-T specific to this therapeutic target», says Dr. Pablo Menéndez, founder of OCI and director of the stem cell biology, developmental leukemia, and immunotherapy group at the Josep Carreras Leukemia Research Institute (IJC). «Seeing now how academic work reaches patients is a dream come true for all of us».

«This is an important milestone and a very proud moment for OneChain and all our partners», said Dr. Stefanos Theoharis, CEO of the company. «Their unending support and commitment to our company and the patients has finally come to bear fruit. My heartfelt thanks go to all those individuals and organizations who have helped us achieve this milestone, including the joint effort of the Josep Carreras Leukemia Research Institute, the OneChain team, the staff at Hospital Clínic and Hospital Sant Joan de Déu, the Josep Carreras Foundation, our main investor, Invivo Partners, the Unoentrecienmil Foundation, the Banc de Sang I Teixits (BST), and the CDTI Innvierte program».

Vincenzo Calvanese: “I want to know what makes a stem cell… a stem cell”

The Josep Carreras Leukaemia Research Institute opens a new lab with the incorporation of Dr. Vincenzo Calvanese, a consolidated researcher on stem cell biology. The new group will try to understand which molecular features and regulatory processes identify a blood stem cell, a fundamental knowledge to advance in many areas, like haematopoietic stem cell transplant, one of the few successful clinical applications of stem cells today.

Dr Vincenzo Calvanese speaks with passion about his research projects and objectives. Trained in pharmaceutical biotechnologies at the University of Bologna, Italy, he moved to Madrid to learn about the epigenetic differentiation of stem cells at the CNIO and the CNB, where he got his PhD. Later on, Calvanese focused his research on haematopoietic (blood) stem cells at the University of California Los Angeles, USA, to finally establish his own lab at the University College London, UK. Now, with a brand-new ERC Consolidator grant in his pocket, one of the finest and most exclusive research funding schemes in Europe, he will open a new lab at the Josep Carreras Institute and will join forces in the fight against leukaemia.

Translational Research joins the best of two worlds: the fundamental knowledge on human biology with the needs for practical innovation for the benefit of patients. Out of pure curiosity, Calvanese is fascinated by the ability of stem cells to become any other cell type, just by using one or another piece of its genetic information. That’s why one of his aims is to understand the molecular determinants of such a special cell type, making a stem cell… a stem cell.

On the practical side, unlocking the potential of blood stem cells will be instrumental to advance in the science of bone marrow transplantation, a life-saving therapy in blood cancers, and to fight against cancer stem cells, the often chemotherapy-resistant cancer cells leading to tumour development and relapse. To do so, the Calvanese lab, established as the «Blood Stem Cell Identity» Lab, will work closely with all his new colleagues at the Josep Carreras Institute, some of whom he knows well already.

«The Josep Carreras Institute harbours a unique mixture of profiles, from the most basic science to the patient-oriented clinical research, all focused on blood cancer. There is a critical mass to start something big», Calvanese explains, and adds that «Barcelona is one of the best science hubs in southern Europe and, for me, it’s like coming home».

But, why another lab on hematopoietic stem cells (HSC)? Well, as Calvanese explains, «HSC existence was experimentally proven more than 60 years ago and, as such, they are a robust platform to study stemness. While there is still debate on the existence of stem cells in other tissues, HSC are really well-characterized, hence one of the best models to study adult stem cell properties, how they are established in the embryo and maintained during life».

His projects are nothing short of ambitions and one of these “approaches” will be to try to recreate in vitro to recreate the complex signals leading to the maturation of stem cells, something never fully reached and instrumental to provide a stable supply of HSCs derived from pluripotent cells for regeneration in the future. To do so, the Calvanese Lab will have the latest technologies at reach, like single cell spatial transcriptomics, state-of-the-art genomics, proteomics and computational analysis.

The institute grows and we could not be happier with the new talent joining our family, being part of our story and helping us reach the day leukaemia will be a 100% curable disease, for everyone. Be welcome, Vincenzo, and best of luck!

El Registro de Donantes de Médula Ósea consigue la certificación mundial por la calidad de su servicio

► El Registro de Donantes de Médula Ósea (REDMO), de la Fundación Josep Carreras, designado por el Ministerio de Sanidad como el único registro de donantes español, acaba de recibir la certificación de la World Marrow Donor Association (WMDA). Esta entidad aglutina a los 101 registros de donantes de médula ósea de todo el mundo.

► Esta certificación internacional reconoce al REDMO como un referente de calidad.

► El REDMO cuenta con 484.175 donantes disponibles, procedentes de todas las comunidades autónomas, y ha hecho posibles 13.576 trasplantes para pacientes de todo el mundo.

► Cada vez más hospitales de todo el mundo eligen a un donante español como el ideal para sus pacientes gracias a la calidad de servicio que ofrece el REDMO.

La certificación obtenida acredita que el REDMO desarrolla cada etapa del proceso de trasplante, desde la captación del donante hasta el seguimiento tras la donación de progenitores al paciente, cumpliendo con los más exigentes estándares internacionales de calidad. Al mismo tiempo, evidencia el máximo cuidado que la Fundación Josep Carreras contra la Leucemia presta al donante para asegurar su seguridad y bienestar.

Mediante este programa, la Fundación consigue ofrecer uno o más donantes compatibles para los pacientes que precisan un trasplante y no disponen de un donante familiar compatible, en un periodo medio de 27 días.

Este reconocimiento supone:

* Una mayor visibilidad de los donantes españoles en las bases de datos nacionales e internacionales.

* Una validación de los procesos internos del REDMO y de las entidades colaboradoras (bancos de cordón, centros autonómicos de donantes, centros hospitalarios de colecta de progenitores hematopoyéticos y centros de trasplante) de todas las comunidades autónomas.

* Una nueva certificación de calidad de los progenitores hematopoyéticos que el REDMO suministra a los pacientes en los centros de trasplante.

En febrero de 2019 se consiguió el primer paso, la «calificación» del REDMO, con una validez de cuatro años. En 2023 se solicitó pasar el siguiente y último paso del proceso, la certificación.

El pasado mes de diciembre, el REDMO recibió la visita de los certificadores internacionales de la World Marrow Donor Association (WMDA), a fin de verificar in situ el rigor del trabajo que este desarrolla en todos los ámbitos: promoción de la donación, colaboración con los centros de donantes implicados, hospitales y equipos de trasplante, registros y hospitales internacionales, servicios de transporte y, muy especialmente, cuidado y atención al donante.

El Instituto de Investigación contra la Leucemia Josep Carreras es acreditado como Centro de Excelencia Severo Ochoa

El Ministerio de Ciencia, Innovación y Universidades ha otorgado la prestigiosa acreditación de Centro de Excelencia Severo Ochoa al Instituto de Investigación contra la Leucemia Josep Carreras, en reconocimiento de su excelencia, impacto científico nacional e internacional y capacidad de atracción de talento, entre otros. Este distintivo sitúa al Instituto de Investigación contra la Leucemia Josep Carreras entre los mejores centros de investigación del Estado.

El Instituto de Investigación contra la Leucemia Josep Carreras, centro CERCA de la Generalitat de Catalunya, ha recibido la resolución de concesión provisional como Centro de Excelencia Severo Ochoa por el Ministerio de Ciencia, Innovación y Universidades.

El Instituto es una de las 10 instituciones que ha recibido la acreditación en la convocatoria 2023, que lo sitúa entre los mejores centros de investigación del Estado en base a la excelencia, las aportaciones científicas, la capacidad de atracción de talento y el impacto económico y social, entre otros.

Este reconocimiento pone de relieve la excelente investigación llevada a cabo, sus colaboraciones continuas y su compromiso con la sociedad, que han dado como resultado la incorporación de centenares de profesionales en los últimos años, la captación de financiación, la sostenibilidad del presupuesto estructural y el liderazgo de grandes proyectos internacionales.

La prestigiosa acreditación Severo Ochoa contribuirá a aumentar la visibilidad internacional del centro, así como el impacto científico, social y económico de los resultados de su investigación. Además, asegura la financiación del nuevo Plan Estratégico del Instituto Josep Carreras, con el objetivo de consolidar sus capacidades y contribuir a su liderazgo científico.

El director del Instituto, el Dr. Manel Esteller, ha expresado su agradecimiento por la acreditación, y comenta que supone “un reconocimiento al trabajo de los últimos cinco años del personal de nuestro joven instituto”. Por su parte, Ana Garrido, directora estratégica y gerente en funciones del Instituto Josep Carreras, valora que “la suma de pequeños esfuerzos se ha traducido en una gran recompensa, un resultado exitoso que representa un antes y uno después para nuestro instituto. Como decía Pablo Neruda, si no escalas la montaña, nunca podrás disfrutar del paisaje. Agradezco a todo el equipo del Instituto haberla escalado con nosotros”.

La selección de los Centros de Excelencia Severo Ochoa se lleva a cabo a través de un riguroso y exigente proceso competitivo, que valora cuestiones como la organización, la financiación, los resultados de la investigación, el liderazgo internacional o la formación.

La acreditación tiene una duración de cuatro años y supone un gran impulso para continuar trabajando, imparables, por una investigación de excelencia que contribuya a la mejora de los resultados y la curación de los pacientes afectados por la leucemia y otras hemopatías malignas.

La Fundación Josep Carreras publica la Guía práctica sobre mieloma múltiple para pacientes y cuidadores

El mieloma múltiple es un cáncer de la sangre menos conocido que la leucemia o los linfomas, pero diagnosticado cada año a más de 3.000 personas en España. Sus afectaciones, su tratamiento y sus secuelas son muy específicas y, a menudo, (con)vivir con el mieloma puede suponer todo un reto.

Hoy presentamos una Guía práctica sobre mieloma múltiple específicamente pensada para el paciente y sus cuidadores.

Desde la Fundación hemos querido no solo explicar en detalle esta enfermedad y sus tratamientos actuales, sino también su impacto tanto físico como emocional. Una visión holística que pretende ver cómo (con)vivir con el mieloma múltiple.

Respecto a temas físicos, en la guía se explican especialmente las lesiones óseas y la neuropatía periférica que son síntomas y secuelas muy características del mieloma múltiple y pueden ser muy dolorosas. Hay ejercicios de fisioterapia y rutinas para ellos, entre otras cosas.

Por lo que atiende a aspectos emocionales, la guía ofrece recursos útiles, grupos de apoyo, trucos para la gestión de la incertidumbre, entre otros temas interesantes.

Otro aspecto que destacar es que también hemos querido tener en cuenta al cuidador ya que él o ella también reciben el impacto de la enfermedad. Por ello, la guía ofrece también trucos y recursos para ayudar a cuidar, para cuidarse para cuidar mejor e incluso temas específicos como las discusiones y la comida o la organización y el trabajo.

Gracias a la colaboración de Pfizer España, hemos podido hacer realidad esta guía para hacer llegar a los pacientes, no solo información rigurosa y acreditada por la dirección médica de nuestra Fundación sobre el mieloma múltiple, sino muchas referencias a vídeos, a podcasts, a otros documentos gráficos, a testimonios, etc.

Descarga la guía AQUÍ

¡Muchas gracias a nuestro colaborador, Pfizer España, por habernos ayudado a que podamos hacer realidad esta guía! Seguimos Imparables también contra el contra el mieloma múltiple.

Researchers find the key to genome-modifying drugs sensitivity in malignant blood diseases

A recent study led by Dr. Manel Esteller, Director of the Josep Carreras Institute, shows how DNA methylation profiling in a common type of blood cancer, myelodysplastic syndrome, predicts whether the patient will respond to treatment. This type of cancer can progress to acute myeloblastic leukaemia, a much more serious disease. The outcomes could help in the early detection of patients who are resistant to demethylating drugs and in the design or administration of alternative treatments.

There are many anti-cancer genes that are no longer active in human tumours, preventing them from carrying out their protective function against cell transformation. One of the main mechanisms used by cancer cells to silence these ‘good’ genes is the addition of a chemical modification called methylation, which results in the loss of gene expression. As this is a simple addition of a single “methyl” group, drugs have been designed to erase this signal and they have already been approved for use in cancer. These hypomethylating drugs are mainly used in malignant blood diseases such as leukaemia.

An article led by Dr. Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute (IJC), ICREA Research Professor and Professor of Genetics at the Faculty of Medicine of the University of Barcelona, published in the British Journal of Haematology, shows how the DNA methylation profiling in common leukaemia predicts whether the patient will respond to treatment.. The groups of Dres. Lurdes Zamora, Blanca Xicoy and Dr Francesc Solé from the Josep Carreras Institute, as well as researchers from the Vall d’Hebron Hospital and the University of Bologna, have also collaborated in the study.

«Our research has analysed nearly 1 million genome methylation signals in patients affected by a type of blood cancer called myelodysplastic syndrome and who have been treated with the demethylating drug. We have found an epigenetic ‘fingerprint’ that is associated with a good clinical response to these drugs, which can help in the early detection of patients who are resistant to demethylating drugs and in the design or administration of alternative treatments», comments Dr Esteller on the article published in the official journal of the British Society of Haematology.

Dr Esteller says they detected general patterns linked to the efficacy of the hypomethylating drug, but also single genes, which could facilitate the development of rapid and relatively inexpensive biomarkers to select responder patients and prepare rescue strategies for the rest. The researcher adds: «The genes we have found give us clues about the mechanisms involved in hypomethylating agents’ sensitivity. Some of them are tumour suppressor genes that now ‘wake up’ to inhibit tumour proliferation, as expected. In other cases, however, what the genes reactivation by the drug is likely to do is to produce proteins (antigens) and other molecules that alert our immune system to fight the disease. These data further support the use of cancer immunotherapy, which is likely to work even better in combination with the use of epigenetic drugs, such as the demethylating drugs included in our study».

Investigadores españoles diseñarán proteínas mediante IA para hacer más eficientes las terapias avanzadas

  • El Ministerio de Ciencia, Innovación y Universidades en colaboración con el Centro para el Desarrollo Tecnológico y de Innovación (CDTI), lo han seleccionado como unos de los 40 proyectos que aborda un reto prioritario para la sociedad y la economía, y lo financiarán con 3,8 millones de euros
  • El proyecto se realizará en un consorcio público-privado formado por VIVEbiotech, Integra Therapeutics y OneChain Immunotherapeutics, la UPF, el IBMB-CSIC y el CIEMAT durante los próximos 4 años

Investigadores de las empresas VIVEbiotech, Integra Therapeutics y OneChain Immunotherapeutics, el Departamento de Medicina y Ciencias de la Vida de la Universidad Pompeu Fabra (UPF), el Instituto de Biología Molecular de Barcelona (IBMB-CSIC) y el Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) se han unido para diseñar con inteligencia artificial y producir partículas virales de nueva generación que se aplicarán en terapias avanzadas. Estas partículas se podrían utilizar en las inmunoterapias, como el tratamiento por CAR-T, para tratar múltiples cánceres y enfermedades raras como la anemia familiar por deficiencia de la piruvato quinasa. 

El proyecto ha sido seleccionado por el Ministerio de Ciencia, Innovación y Universidades y el Centro para el Desarrollo Tecnológico y de Innovación (CDTI) después de valorar el impacto que puede generar en la salud, se llevará a cabo entre 2024 y 2027, y recibirá una financiación 3,8 millones de euros en el marco del programa TransMisiones.

«Estamos contentos de anunciar esta alianza con empresas y centros de investigación españoles con amplio conocimiento y experiencia en toda la cadena de valor en la investigación, desarrollo y fabricación de terapias avanzadas para el tratamiento de enfermedades raras y oncología» comenta el Dr. Gurutz Linazasoro, CEO de VIVEbiotech. VIVEbiotech, con sede en San Sebastián, es una compañía especializada en el desarrollo y la fabricación de vectores lentivirales.

La Dra. Avencia Sánchez-Mejías, CEO y cofundadora de Integra Therapeutics, compañía que desarrolla herramientas de escritura genética en Barcelona, explica que incorporar la IA como aliada en la terapia celular tiene un gran potencial: «Los algoritmos de IA que se utilizan para el procesamiento de textos, por ejemplo con ChatGTP, también se pueden aplicar en biología. La herramienta que crearemos nos permitirá diseñar nuevas secuencias de ADN y nuevas funciones de proteínas que antes no eran factibles, y obtener más rápidamente un producto terapéutico universal para una enfermedad específica».

La terapia celular es una técnica importante para el tratamiento de enfermedades complejas o de mal pronóstico. Tradicionalmente la terapia celular se ha realizado en células extraídas de los pacientes que, después de ser modificadas en el laboratorio, son readministradas al paciente.

«Con el avance que proponemos, la terapia CAR-T podrá llevarse a cabo directamente dentro del paciente, administrándole estos nuevos vectores virales, lo que representa importantes ventajas respecto a la manufactura ex vivo en ahorro de tiempo y coste y también en comodidad para el paciente que ya no tendrá que someterse a la aféresis, es decir, a la extracción de sus células» explica el Dr. Víctor Manuel Díaz, director Científico de OneChain Immunotherapeutics. OneChain Immunotherapeutics es una spin-off del Instituto Josep Carreras que desarrolla terapias CAR-T para enfermedades oncológicas.

«Mediante la aplicación de la IA con técnicas de evolución dirigida, optimizaremos la eficiencia y precisión del proceso de identificación, dirección y entrega de las nuevas partículas virales a células concretas del organismo del paciente para que actúen, únicamente, en aquellas células que necesitan ser tratadas» detalla el Dr. Marc Güell, que dirige el Laboratorio de Biología Sintética Traslacional en la UPF.

Por su parte, el grupo de Inteligencia Artificial para el Diseño de Proteínas de la Dra. Noelia Ferruz en el IBMB-CSIC se centrará en la implementación de modelos de lenguaje para la generación de proteínas con propiedades a la carta. «Estos modelos mejorarán retroalimentándose con los resultados obtenidos por el resto de miembros del consorcio, alcanzando cada vez eficiencias más elevadas» ha comentado Ferruz.

La vehiculización de las herramientas de terapia génica y edición génica es, seguramente, el reto más importantes en el desarrollo de alternativas terapéuticas eficaces cuando la célula diana a modificar es la célula madre hematopoyética. «La generación de vectores eficaces para la modificación genética de células madre hematopoyéticas nos permitirá abordar un número importante de enfermedades raras, sin una cura eficaz a día de hoy, y que son devastadoras para los pacientes afectos y todo su entorno familiar y social» comenta el Dr. José-Carlos Segovia, jefe de la División de Tecnología Celular en el CIEMAT.

Aunque este proyecto se focalizará en hacer más seguras y eficientes las inmunoterapias que se usan para tratar cánceres y la edición de células madre hematopoyéticas, que permitirá tratar enfermedades raras cómo las anemias familiares hereditarias, en un futuro, esta técnica se podría aplicar para el tratamiento de enfermedades autoinmunes y el envejecimiento.

OneChain Immunotherapeutics receives support to advance a new promising CAR T therapy for a rare leukaemia with no therapeutic alternatives

A consortium led by OneChain Immunotherapeutics, spin-off of the Josep Carreras Institute, receives support from the Spanish Ministry of Science, Innovation and Universities to advance a groundbreaking therapy for acute lymphoblastic leukaemia type T into clinical phase. The therapy, based on CAR T technology, targets two new therapeutic markers with minimal presence in healthy tissues, enhancing treatment efficacy and the number of treatable patients.

The consortium led by the company OneChain Immunotherapeutics (OCI), spin-off of the Josep Carreras Institute (IJC) and Dr. Pablo Menéndez, has received support from the Spanish Ministry of Science, Innovation and Universities to bring an innovative therapy to the clinical phase. This therapy could treat up to 80% of patients with T-cell acute lymphoblastic leukaemia (T-ALL), a rare condition with few therapeutic options, affecting children (60%) and adults. The project, set to last three years, will involve collaboration with the IJC and the Blood and Tissue Bank (Banc de Sang i Teixits).

The treatment of acute lymphoblastic leukaemia type T, one of the most aggressive forms of leukaemia, has historically relied on intensive chemotherapy. Despite improvements in survival rates, this therapy results in devastating effects for patients. Furthermore, a significant percentage of them do not respond to treatment. «For patients who have experienced a relapse, finding effective treatments is particularly challenging,» explains Dr. Víctor M. Díaz, research director at the company, «our therapy brings hope to these patients».

OCI’s approach is based on CAR-T technology, a type of immunotherapy that involves extracting immune cells from the patient to modify them in the laboratory, enhancing their ability to recognize and attack cancer cells and has shown great promise in other forms of leukaemia and lymphoma. «Our aim is to develop this therapy over the three years of the project to initiate a first clinical trial in humans», Dr. Díaz adds.


Attacking the same cell through different targets
The therapy developed by OCI will simultaneously target two markers present on cancer cells, making it more effective than single-target therapies and expanding the number of treatable patients. CAR T therapy has not yet become a consolidated option against T-cell leukaemia, such as T-ALL, because tumour and healthy T cells exhibit almost the same molecules on their surface. As a result, CAR T therapies aimed at T-ALL destroy both types of cells, leading to severe immunosuppression in patients.

OCI has already developed a CAR-T therapy directed at the CD1a protein, a safe target with little presence in healthy cells. However, this molecule is present in cortical T-ALL (coT-ALL), a subset of T-ALL, representing only 30-40% of T-ALL patients. «The first CAR T therapy we developed, targeting the CD1a antigen, is already in clinical trials, demonstrating its safety and efficacy for a specific group of patients», Dr. Díaz explains. «By incorporating a second target into our strategy, we do not only increase the percentage of patients we could treat—up to 80%—but also enhance the effectiveness of the therapy».

The grant has been awarded in the call for public-private collaboration projects by the Spanish Ministry of Science and Innovation.It is the result of recognition awarded to projects that have already reached an advanced phase of development and are ready to transition to clinical application. «We are in a unique position to make a real difference in the lives of patients, expanding our therapies to include those who previously had few options», Dr. Díaz says.


Acute Lymphoblastic Leukaemia Type T: A Rare Disease
Acute lymphoblastic leukaemia (ALL) is a type of cancer affecting the bone marrow, the soft tissue within our bones where blood cells are produced. It is characterized by the excessive production of immature lymphocytes (white blood cells) that do not function properly. These abnormal lymphocytes rapidly multiply, interfering with the production of healthy blood cells and can spread within a few months to different parts of the body, such as the lymphatic system, liver, or spleen.

It is an aggressive and uncommon cancer, with an incidence of around 1.5 cases per 100,000 inhabitants in high-income countries. Depending on the affected cell type, there are two types of ALL, B-cell ALL (ALL-B) and T-cell ALL (ALL-T). The latter, which this new therapy targets, is even rarer, with about 100 cases diagnosed per year in Spain, accounting for approximately 10-15% of all acute leukaemia in children and between 20-25% in adults.

It is a highly heterogeneous disease with many subtypes, which complicates research and the development of effective treatments. Therefore, innovation and the development of targeted therapies are essential to increase treatment options for these patients.

Awakening leukaemic stem cells to make them sensitive to chemotherapy

Researchers from the Josep Carreras Leukaemia Research Institute found that inhibiting the hypoxia response in childhood Acute Myeloid Leukaemia tumours help sensitize leukaemic stem cells, those expanding the tumour, to Cytarabine, the standard of choice chemotherapy. Leukaemic stem cells activate the hypoxia system in the bone marrow to endure its natural low oxygen concentration, making them resistant to anticancer drugs. The results, obtained in vitro and in vivo, pave the way towards an efficient new combinatorial treatment for patients, after diagnosis or relapse.

Acute Myeloid Leukaemia (AML) is the most common leukaemia in adults, but a rare disease among children. Despite childhood AML has an incidence of around 7 cases per million in developed countries, with an overall survival around 75%, there is still room for improvement: up to 40% of the children relapse, with roughly a 30% probability of long-term survival.

AML progression relies on a specific subset of very scarce cells called Leukaemic Stem Cells (LSC), found in the bone marrow, that are resistant to standard of choice chemotherapy, such as cytarabine, leading to relapse after an apparently successful treatment. Previous research found that LSC happen to be in a dormant state due to the low concentration of oxygen in the bone marrow (hypoxia conditions) and that could greatly explain their resistance.

In a recent publication at the journal HemaSphere, an official journal of the European Hematology Association, researchers from the Menéndez Lab at the Josep Carreras Leukaemia Research Institute found that treating the tumour cells with an inhibitor of the hypoxia response would sensitize LSC to Cytarabine and help significantly reduce the population of these cancer-promoting cells, both in vitro and in vivo. The research was a joint collaboration between the Menéndez Lab and researchers from other institutions in Spain, France, The Netherlands and Australia.

The team, spearheaded by Dr. Talia Velasco (former member of the Menéndez Lab), used state-of-the-art technology to identify high-risk childhood AML patients and analyse the transcriptional profile of thousands of individual leukaemic cells. The analysis showed that the hypoxia cellular system was overactivated in virtually all leukaemic cells compared with healthy cells. They then tested the sensitivity to cytarabine with and without BAY87-2243, an inhibitor of the hypoxia system, in cultured cells and in real tumours engrafted in specially produced lab mice.

The results showed that the combination of both drugs enhanced the effectivity of the treatment, with significant reductions of leukaemic cells. A few drawbacks should be addressed before the combinatorial approach becomes a reality in the clinic, since the delivery of drugs at the bone marrow is low and the potential interactions should be sorted out before. However, with the drugs already in the market, or very close to it, it should not take too long to figure it out and add a new bullet in the arsenal to fight against childhood acute myeloid leukaemia.

The research was funded thanks to the contributions of the MSCA H2020 program by the EU, the Asociación Española contra el Cáncer and the Deutsche Jose Carreras Stiftung.

The Bigas Lab finds Notch self-inhibition keeps haematopoietic stem cells from differentiate

A collaborative effort led by Dr. Anna Bigas, from the Hospital del Mar Research Institute and Josep Carreras Leukaemia Research Institute, found that the population of haematopoietic stem cells (HSC) responsible for the generation and self-renewal of the blood and immune system keeps a long-term undifferentiated state thanks to its ability to physically block its own NOTCH1 receptor through the expression of JAGGED1, a specific NOTCH activator. Authors hypothesise that the lack of this previously unknown mechanism might be the cause for the poor performance of current approaches to generate HSC from induced pluripotent stem cells for regenerative medicine.

We all originate from a single cell, that multiplies over and over again to produce every tissue in our body and keep them healthy and working. This has two consequences: first, many of these cells must change, differentiate, to develop the specific functions of each tissue. Doing so, they lose the capacity to become other types of cells. Second, some cells must remain undifferentiated to regenerate and heal the tissue when needed. This is especially important in the blood, a tissue that continuously regenerates.

The question is, how does a cell know when to keep undifferentiated and when to move on? The simple answer is they tell each other. There is an intense crosstalk between cells in a tissue, and most of it comes from interactions through a protein on its surface, called NOTCH1. In some cells, when this protein binds to their ligands onto other cells, the message is to differentiate. Scientists have been trying to understand how undifferentiated cells ignore all this chatter while expressing NOTCH1.

In a recent paper published at the top journal Nature Communications, a team led by Dr. Anna Bigas, group leader at the Josep Carreras Leukaemia Research Institute and the Hospital del Mar Research Institute, found that the nondifferentiated Haematopoietic Stem Cells (HSC) block their own NOTCH1 protein with the protein JAGGED1, effectively isolating themselves from their cellular background. The findings have been possible thanks to the use of state-of-the-art technology, especially single-cell RNA sequencing and new imaging of protein interactions.

Also, the results of the analysis found that the interactions between NOTCH1 and JAGGED1 were far from being spontaneous, but a part of a predetermined cellular pathway. Indeed, they found a third protein, FRINGE, that fine-tuned the interacting regions of NOTCH1 and JAGGED to improve their contact areas and facilitate the binding.

aken together, the reported findings could explain why the efforts to grow a large population of stem cells in vitro for regenerative medicine fail to yield cells with the capacity to self-renew and differentiate in the long-term. Understanding and mimicking this cellular mechanism can pave the way for new advances in generating Hematopoietic stem cells.

The research team was spearheaded by Dr. Roshana Thambyrajah, at the Bigas-Espinosa Lab, and counted with the collaboration of Dr. Eduard Porta and Dr. Manel Esteller’s groups at the Josep Carreras Institute, the Wellcome-MRC Cambridge Stem Cell Institute, the University of Manchester, Centro Nacional de Investigaciones Cardiovasculares and the Bellvitge Institute for Biomedical Research. The work is also a collaboration with the Spanish networks CIBERONC and CIBER-BBN.