Tavira, B. (Beatriz)

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    The complement system as a regulator of tumor-promoting activities mediated by myeloid-derived suppressor cells
    (Elsevier, 2022) Tavira, B. (Beatriz); Pio, R. (Rubén); Senent, Y. (Yaiza); Ajona, D. (Daniel)
    Tumor progression relies on the interaction between tumor cells and their surrounding tumor microenvironment (TME), which also influences therapeutic responses. The complement system, an essential part of innate im- munity, has been traditionally considered an effector arm against tumors. However, established tumors co-opt complement-mediated immune responses in the TME to support chronic inflammation, activate cancer-related signaling pathways and hamper antitumor immune responses. In this context, myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid progenitors with immunosuppressive functions, are recognized as major mediators of tumor-associated complement activities. This review focuses on the impact of complement activation within the TME, with a special emphasis on MDSC functions and the involvement of the C5a/C5aR1 axis. We also discuss the translation of these findings into therapeutic advances based on comple- ment inhibition.
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    Plasma fractalkine contributes to systemic myeloid diversity and PD-L1/PD-1 blockade in lung cancer
    (2023) Tavira, B. (Beatriz); Fernández, L. (Leticia); Kochan, G. (Grazyna); Pio, R. (Rubén); Chocarro, L. (Luisa); Ventura, A. (Alfonso); Alfaro-Arnedo, E. (Elvira); Remirez, A. (Ana); Gotera-Rivera, C. (Carolina); Bocanegra, A. (Ana); Ajona-Martínez-Polo, D. (Daniel); Recalde, N. (Nerea); Piñeiro-Hermida, S. (Sergio); Pichel, J.G. (José G.); Zuazo, M. (Miren); Morilla, I. (Idoia); Fernández-Hinojal, G. (Gonzalo); Blanco, E. (Ester); Echaide, M. (Miriam); Montuenga-Badia, L.M. (Luis M.); Morente, P. (Pilar); Escors, D. (David); Garnica, M. (Maider); Martinez-Aguillo, M. (M.); Roncero, A. (Alejandra); Vera, R. (Ruth); Lasarte, J.J. (Juan José)
    Recent studies highlight the importance of baseline functional immunity for immune checkpoint blockade therapies. High-dimensional systemic immune profiling is performed in a cohort of non-small-cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders show high baseline myeloid phenotypic diversity in peripheral blood. To quantify it, we define a diversity index as a potential biomarker of response. This parameter correlates with elevated activated monocytic cells and decreased granulocytic phenotypes. High-throughput profiling of soluble factors in plasma identifies fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of response to immunotherapy that also correlates with myeloid cell diversity in human patients and murine models. Secreted FKN inhibits lung adenocarcinoma growth in vivo through a prominent contribution of systemic effector NK cells and increased tumor immune infiltration. FKN sensitizes murine lung cancer models refractory to anti-PD-1 treatment to immune checkpoint blockade immunotherapy. Importantly, recombinant FKN and tumor-expressed FKN are efficacious in delaying tumor growth in vivo locally and systemically, indicating a potential therapeutic use of FKN in combination with immunotherapy.
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    Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma
    (Massachusetts Medical Society, 2022) Tavira, B. (Beatriz); Patiño-García, A. (Ana); Stunnenberg, H. (Henk); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Zalacain, M. (Marta); Martinez-Velez, N. (Naiara); Robbins, J. (Joan); Lang, F.F. (Frederick F.); Ewald, B. (Brett); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Cruz, O. (Ofelia); Esparragosa-Vázquez, I. (I.); Astigarraga, I. (Itziar); Marrodán, L. (Lucía); Villalba, M. (María); Alkorta-Aranburu, G. (Gorka); Oscoz-Lizarbe, M. (Miren); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Hervas-Stubbs, S. (Sandra); Dobbs, J. (Jessica); Lugt, J. (Jasper) van der; Puigdelloses-Vallcorba, M. (Montserrat); Idoate, M.A. (Miguel Ángel); Dharmadhikari, G. (Gitanjali); Lopez-Ibor, B. (Blanca); Andrea, C.E. (Carlos Eduardo) de; Labiano, S. (Sara); Hulleman, E. (Esther); Tamayo, I. (Ibon); Laspidea, V. (Virginia); Hernandez-Alcoceba, R. (Rubén); Fueyo, J. (Juan); Gallego-Perez-Larraya, J. (Jaime); Ruiz-Moreno, C. (Cristian); Nuñez-Cordoba, J.M. (Jorge M.); Jones, C. (Chris)
    Background: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. Methods: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. Results: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. Conclusions: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).