Progenitors and cell therapy
Although more than half of children diagnosed with cancer survive, cancer remains the leading cause of death from disease in children under the age of 14. The reality for patients with metastasis at diagnosis or those who have poor genetic markers of prognosis or recurrent/refractory tumours, is very negative. New treatment options are therefore necessary for such patients. Our interest is in trying to develop treatment strategies for children with poor prognosis, based on immunotherapy strategies against cancer.
We propose developing treatment strategies for children with poor prognosis malignant tumours, based on the use of immune cells capable of attacking and eliminating cancer cells. This is a project that has both clinical and preclinical aspects, and is orientated towards haematological malignancies as well as solid tumours. For children with leukaemia, we propose evaluating the administration of NK cells from the donor one month after receiving a haploidentical transplant. Our current experience has allowed us to identify that the reconstitution of an insufficient number of NK cells one month after transplantation is a factor significantly associated with leukaemia relapse. Administering NK cells to this group of children could therefore increase the clinical benefit of transplantation.
In the case of solid tumours, we intend to evaluate a treatment that has not been tried in children with cancer, but which has demonstrated anti-tumour capacity, especially in melanomas. It consists of using tumour infiltrating lymphocytes (TILs) as antitumour therapy. This clinical research plan is accompanied by a parallel experimental research plan aimed at preparing a tumour immunotherapy product capable of overcoming the barriers imposed by tumours on effector cells, known as tolerance. Of the several known mechanisms that produce tolerance, we will begin by addressing the soluble molecules that induce a decrease in the cytotoxic capacity of both NK and TIL cells.
We intend to generate effector cells resistant to the action of these immunoregulatory molecules, and establish protocols that are immediately transferable to the clinic. These cellular manipulation strategies aim to be a proof of concept and will therefore be evaluated in pre-clinical models, serving as a "master protocol" to apply to other known molecules or as a foundation for generating new knowledge. These results should serve to help design new clinical trials for the continuation of the project.
The team is a multidisciplinary group, with proven experience in the diagnosis and treatment of childhood cancer, and in the development of research projects into advanced therapies applied to paediatric drug-resistant cancer, and the development of clinical trials in paediatric oncology. It also has all the technical means and infrastructure for the development of our projects, ensuring implementation in patients, which would have a potential impact on all children treated in any paediatric oncology unit in Spain.
Team members
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Group leader: Luis Madero López Hospital Infantil Universitario Niño Jesús |
Other team members:
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Ramirez Orellana, Manuel. Búsqueda de biomarcadores asociados a la respuesta clínica en niños con cáncer tratados con Celyvir. PI16/02008. ISCIII. 2017-2019.
This grant is funded by the 2013-2016 Spanish Science, Technology and Innovation Research Plan and the ISCIII – Subdirectorate General for Evaluation and Promotion of Research – and co-financed by the European Regional Development Fund, Operational Programme Smart Growth 2014-2020 according to Regulation (EU) no. 1303/2013.
Moreno Martín, Lucas Retortillo. Desarrollo de nuevos fármacos y biomarcadores para alteraciones moleculares recurrentes de ALK, RAS/RAF/MAPK/MEK, TERT y CHK1 en neuroblastoma de alto riesgo. PI16/02114. ISCIII. 2017-2019.
Screening in vitro para identificar las combinaciones de fármacos frente a dianas terapéuticas más efectivas e identificar biomarcadores predictivos en muestras de pacientes.
This grant is funded by the 2013-2016 Spanish Science, Technology and Innovation Research Plan and the ISCIII – Subdirectorate General for Evaluation and Promotion of Research – and co-financed by the European Regional Development Fund, Operational Programme Smart Growth 2014-2020 according to Regulation (EU) no. 1303/2013.
Ramírez Orellana, Manuel. Estudio de los mecanismos de acción de la terapia con CELVIR en tumores infantiles: hacia la optimización de los resultados clínicos. PI13/02487. ISCIII. 2014-2016
Madero López, Luis. Identificación y validación de biomarcadores de recaída infantil LLA leucemia. PI13/02475. ISCIII. 2014-2016.
Ramírez Orellana, Manuel. CELLCAM: Una nueva generación de medicamentos celulares más eficaces y seguros. S2010/BMD-2420. CAM. 2012-2015.
Ramírez Orellana, Manuel. Papel de BMP4 en Leucemia Linfoblástica Aguda Infantil: factor pronóstico y función en la recaída. Fundación uno entre cien mil. 2015-2017.
Ramirez Orellana, Manuel. VISION: Visual privacy management in user centric open environments. 653642. European Commission. 2015-2017.
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Baskin JL, Lezcano E, Kim BS, Figueredo D, Lassaletta A, Perez-Martinez A, Madero L, Caniza MA, Howard SC, Samudio A, Finlay JL. Management of children with brain tumours in Paraguay. Neuro-Oncology 2013. 15: 235-241. FI: 5.286(Q1). PMID: 23197688. DOI: 10.1093/neuonc/nos291.
Martínez-Laperche C, Gómez-García AM, Lassaletta Á, Moscardó C, Vivanco JL, Molina J, Fuster JL, Couselo JM, de Toledo JS, Bureo E, Madero L, Ramírez M. Detection of occult cerebrospinal fluid involvement during maintenance therapy identifies a group of children with acute lymphoblastic leukemia at high risk for relapse. Am. J. Hematol. 2013. 88: 359-364. FI: 3.477(Q1). PMID: 23468276. DOI: 10.1002/ajh.23407.
Castella, Maria, Pujol, Roser, Callen, Elsa, Ramirez, Maria J., Casado, Jose A., Talavera, Maria, Ferro, Teresa, Munoz, Arturo, Sevilla, Julian, Madero, Luis, Cela, Elena, Belendez, Cristina, Diaz de Heredia, Cristina, Olive, Teresa, Sanchez de Toledo, Jose, Badell, Isabel, Estella, Jesus, Dasi, Angeles, Rodriguez-Villa, Antonia, Gomez, Pedro, Tapia, Maria, Molines, Antonio, Figuera, Angela, Bueren, Juan A., Surralles, Jordi. Chromosome fragility in patients with Fanconi anaemia: diagnostic implications and clinical impact. J Med Genet 2011. 48: 242-250. FI: 6.365(Q1). PMID: 21217111. DOI: 10.1136/jmg.2010.084210.
Castella, Maria, Pujol, Roser, Callen, Elsa, Trujillo, Juan P., Casado, Jose A., Gille, Hans, Lach, Francis P., Auerbach, Arleen D., Schindler, Detlev, Benitez, Javier, Porto, Beatriz, Ferro, Teresa, Munoz, Arturo, Sevilla, Julian, Madero, Luis, Cela, Elena, Belendez, Cristina, Diaz de Heredia, Cristina, Olive, Teresa, Sanchez de Toledo, Jose, Badell, Isabel, Torrent, Montserrat, Estella, Jesus, Dasi, Angeles, Rodriguez-Villa, Antonia, Gomez, Pedro, Barbot, Jose, Tapia, Maria, Molines, Antonio, Figuera, Angela, Bueren, Juan A., Surralles, Jordi. Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations. Blood 2011. 117: 3759-3769. FI: 9.898(Q1). PMID: 21273304. DOI: 10.1182/blood-2010-08-299917.
