Naiara Martinez Velez

All Publications

• Combination of locoregional radiotherapy with a TIM-3 aptamer improves survival in diffuse midline glioma models. JCI insight Ausejo-Mauleon, I., Martinez-Velez, N., Lacalle, A., de la Nava, D., Cebollero, J., Villanueva, H., Casares, N., Marco-Sanz, J., Laspidea, V., Becher, O., Patiño-García, A., Labiano, S., Pastor, F., Alonso, M. M. 2024; 9 (18)

  Abstract

  Pediatric diffuse midline gliomas (DMG) with altered H3-K27M are aggressive brain tumors that arise during childhood. Despite advances in genomic knowledge and the significant number of clinical trials testing new targeted therapies, patient outcomes are still poor. Immune checkpoint blockades with small molecules, such as aptamers, are opening new therapeutic options that represent hope for this orphan disease. Here, we demonstrated that a TIM-3 aptamer (TIM-3 Apt) as monotherapy increased the immune infiltration and elicited a strong specific immune response with a tendency to improve the overall survival of treated DMG-bearing mice. Importantly, combining TIM-3 Apt with radiotherapy increased the overall median survival and led to long-term survivor mice in 2 pediatric DMG orthotopic murine models. Interestingly, TIM-3 Apt administration increased the number of myeloid populations and the proinflammatory CD8-to-Tregs ratios in the tumor microenvironment as compared with nontreated groups after radiotherapy. Importantly, the depletion of T cells led to a major loss of the therapeutic effect achieved by the combination. This work uncovers TIM-3 targeting as an immunotherapy approach to improve the radiotherapy outcome in DMGs and offers a strong foundation for propelling a phase I clinical trial using radiotherapy and TIM-3 blockade combination as a treatment for these tumors.

  View details for DOI 10.1172/jci.insight.175257

  View details for PubMedID 39146023

• TIM-3 TARGETED APTAMER IN COMBINATION WITH LOCO-REGIONAL RADIOTHERAPY IMPROVES SURVIVAL BY MODULATING THE IMMUNE INFILTRATION IN DIFFUSE MIDLINE GLIOMA MODELS Ausejo-Mauleon, I., de la Nava, D., Martinez-Velez, N., Nuin, S., Morales, S., Palacios-Alonso, D., Pastor, F., Alonso, M. M. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae064.066

  View details for Web of Science ID 001252720000367

• Engineered CD47 protects T cells for enhanced antitumour immunity. Nature Yamada-Hunter, S. A., Theruvath, J., McIntosh, B. J., Freitas, K. A., Lin, F., Radosevich, M. T., Leruste, A., Dhingra, S., Martinez-Velez, N., Xu, P., Huang, J., Delaidelli, A., Desai, M. H., Good, Z., Polak, R., May, A., Labanieh, L., Bjelajac, J., Murty, T., Ehlinger, Z., Mount, C. W., Chen, Y., Heitzeneder, S., Marjon, K. D., Banuelos, A., Khan, O., Wasserman, S. L., Spiegel, J. Y., Fernandez-Pol, S., Kuo, C. J., Sorensen, P. H., Monje, M., Majzner, R. G., Weissman, I. L., Sahaf, B., Sotillo, E., Cochran, J. R., Mackall, C. L. 2024

  Abstract

  Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.

  View details for DOI 10.1038/s41586-024-07443-8

  View details for PubMedID 38750365

  View details for PubMedCentralID 4182950

• Local treatment of a pediatric osteosarcoma model with a 4-1BBL armed oncolytic adenovirus results in an antitumor effect and leads to immune memory. Molecular cancer therapeutics Martinez-Velez, N., Laspidea, V., Zalacain, M., Labiano, S., Garcia-Moure, M., Puigdelloses, M., Marrodan, L., Gonzalez-Huarriz, M., Herrador, G., de la Nava, D., Ausejo-Mauleon, I., Fueyo, J., Gomez-Manzano, C., Patino-Garcia, A., Alonso, M. M. 1800

  Abstract

  Osteosarcoma is an aggressive bone tumor occurring primarily in pediatric patients. Despite years of intensive research, the outcomes of patients with metastatic disease or who do not respond to therapy have remained poor and have not changed in the last 30 years. Oncolytic virotherapy is becoming a reality to treat local and metastatic tumors while maintaining a favorable safety profile. Delta-24-ACT is a replicative oncolytic adenovirus engineered to selectively target cancer cells and to potentiate immune responses through expression of the immune costimulatory ligand 4-1BB. This work aimed to assess the antisarcoma effect of Delta-24-ACT. MTS and replication assays were used to quantify the antitumor effects of Delta-24-ACT in vitro in osteosarcoma human and murine cell lines. Evaluation of the in vivo antitumor effect and immune response to Delta-24-ACT was performed in immunocompetent mice bearing orthotopic K7M2 cell line. Immunophenotyping of the tumor microenvironment was characterized by immunohistochemistry and flow cytometry. In vitro, Delta-24-ACT killed osteosarcoma cells and triggered the production of danger signals. In vivo, local treatment with Delta-24-ACT led to antitumor effects against both the primary tumor and spontaneous metastases in a murine osteosarcoma model. Viral treatment was safe, with no noted toxicity. Delta-24-ACT significantly increased the median survival time of treated mice. Collectively, our data identify Delta-24-ACT administration as an effective and safe therapeutic strategy for local and metastatic osteosarcoma. These results support clinical translation of this viral immunotherapy approach.

  View details for DOI 10.1158/1535-7163.MCT-21-0565

  View details for PubMedID 34965961

• The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. Nature communications Martinez-Velez, N., Garcia-Moure, M., Marigil, M., Gonzalez-Huarriz, M., Puigdelloses, M., Gallego Perez-Larraya, J., Zalacain, M., Marrodan, L., Varela-Guruceaga, M., Laspidea, V., Aristu, J. J., Ramos, L. I., Tejada-Solis, S., Diez-Valle, R., Jones, C., Mackay, A., Martinez-Climent, J. A., Garcia-Barchino, M. J., Raabe, E., Monje, M., Becher, O. J., Junier, M. P., El-Habr, E. A., Chneiweiss, H., Aldave, G., Jiang, H., Fueyo, J., Patino-Garcia, A., Gomez-Manzano, C., Alonso, M. M. 2019; 10 (1): 2235

  Abstract

  Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).

  View details for DOI 10.1038/s41467-019-10043-0

  View details for PubMedID 31138805

• DELTA-24-RDG AS AN ALTERNATIVE THERAPEUTIC TOOL FOR pHGG/DIPG Martinez-Velez, N., Xipell, E., Jiang, H., Gomez-Manzano, C., Fueyo, J., Junier, M., Chneiweiss, H., El Habr, E., Monje, M., Becher, O., Alonso, M. M. OXFORD UNIV PRESS INC. 2015: 15

  View details for Web of Science ID 000361304800060