Perez, G. (Guiomar)
- Publications
- item.page.relationships.isContributorAdvisorOfPublication
- item.page.relationships.isContributorOfPublication
6 results
Search Results
Now showing 1 - 6 of 6
- Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients(Elsevier, 2018) Berraondo, P. (Pedro); Gil-Bazo, I. (Ignacio); Salazar, A.M. (A. M.); Alfaro, C. (Carlos); Perez-Gracia, J.L. (Jose Luis); Martin-Algarra, S. (Salvador); Rodriguez, I. (Inmaculada); Rodriguez-Ruiz, M.E. (María Esperanza); Lopez-Diaz-de-Cerio, A. (Ascensión); Barbes-Fernandez, B. (Benigno); Oñate, C. (Carmen); Inoges, S. (Susana); Gurpide, A. (Alfonso); Ponz-Sarvise, M. (Mariano); Melero, I. (Ignacio); Benito, A. (Amparo); Perez, G. (Guiomar); Andrea, C.E. (Carlos Eduardo) de; Resano, L. (Leyre); Fernandez-Sanmamed, M. (Miguel)Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-a and IFN-a. On days þ8 and þ10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and posttreatment PBMC from patients achieving durable stable disease (SD) were studied by IFNc ELISPOT-assays responding to tumor-lysate loaded DC and by TCRb sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABRþ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-b and IFN-a mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1b concentrations, especially in patients presenting SD. IFNc-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.
- Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins(AACR, 2014) Mazzolini, G. (Guillermo); Alfaro, C. (Carlos); Rizzo, M. (Manglio); Perez-Gracia, J.L. (Jose Luis); Munoz-Calleja, C. (Cecilia); Martin-Algarra, S. (Salvador); Rodriguez, I. (Inmaculada); Rodriguez-Ruiz, M.E. (María Esperanza); Carranza, O. (Omar); Fernández-Landázuri, S. (Sara); Lopez-Picazo, J.M. (José M.); Sangro, B. (Bruno); Oñate, C. (Carmen); Andueza, M.P. (Maria P.); Melero, I. (Ignacio); Gross, S. (Stefanie); Perez, G. (Guiomar); González, Á. (Álvaro); Pascual, J.I. (Juan Ignacio); Fernandez-Sanmamed, M. (Miguel)Purpose: Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden. Experimental Design:IL8levels were monitored by sandwich ELISAsin cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis. Results: IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n ¼ 16), renal cell carcinoma (RCC; n ¼ 23), non–small cell lung cancer (NSCLC; n ¼ 21), or hepatocellular carcinoma (HCC; n ¼ 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n ¼ 16; RCC, n ¼ 23; HCC, n ¼ 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n ¼ 16) and immunomodulatory monoclonal antibodies (melanoma, n ¼ 8). IL8 concentrations in urine (n ¼ 18) were mainly elevated in tumors with direct contact with the urinary tract. Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance.
- Immunotherapeutic effects of intratumoral nanoplexed poly I:C(BMC, 2019) Planelles, M. (María); Etxeberria, I. (Iñaki); Perez-Gracia, J.L. (Jose Luis); Rodriguez, I. (Inmaculada); Bolaños, E. (Elixabet); Rodriguez-Ruiz, M.E. (María Esperanza); Aznar, M.A. (María Ángela); Marquez-Rodas, I. (Iván); Garasa, S. (Saray); Quintero, M. (Marisol); Lopez-Casas, P. (Pedro); Molina, C. (Carmeen); Melero, I. (Ignacio); Perez, G. (Guiomar); Perez-Olivares, M. (Mercedes); Teijeira, A. (Álvaro)Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and which upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment with BO-112 of subcutaneous tumors derived from MC38, 4 T1 and B16- F10 leads to remarkable local disease control dependent on type-1 interferon and gamma-interferon. Some degree of control of non-injected tumor lesions following BO-112 intratumoral treatment was found in mice bearing bilateral B16-OVA melanomas, an activity which was enhanced with co-treatment with systemic anti-CD137 and anti-PD-L1 mAbs. More abundant CD8+ T lymphocytes were found in B16-OVA tumor-draining lymph nodes and in the tumor microenvironment following intratumoral BO-112 treatment, with enhanced numbers of tumor antigen-specific cytotoxic T lymphocytes. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Inspired by these data, intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098).
- Dendritic cells take up and present antigens from viable and apoptotic polymorphonuclear leukocytes(Public Library of Science, 2011) Martinez-Forero, I. (Iván); Alfaro, C. (Carlos); Perez-Gracia, J.L. (Jose Luis); Rodriguez, I. (Inmaculada); Bolaños, E. (Elixabet); Morales-Kastresana, A. (Aizea); Gonzalez-Hernandez, A. (Alvaro); Oñate, C. (Carmen); Hervas-Stubbs, S. (Sandra); Melero, I. (Ignacio); Palazon, A. (Asís); Perez, G. (Guiomar); Suarez, N. (Natalia); Fernandez-Sanmamed, M. (Miguel)Dendritic cells (DC) are endowed with the ability to cross-present antigens from other cell types to cognate T cells. DC are poised to meet polymorphonuclear leukocytes (PMNs) as a result of being co-attracted by interleukin-8 (IL-8), for instance as produced by tumor cells or infected tissue. Human monocyte-derived and mouse bone marrow-derived DC can readily internalize viable or UV-irradiated PMNs. Such internalization was abrogated at 4°C and partly inhibited by anti-CD18 mAb. In mice, DC which had internalized PMNs containing electroporated ovalbumin (OVA) protein, were able to cross-present the antigen to CD8 (OT-1) and CD4 (OT-2) TCR-transgenic T cells. Moreover, in humans, tumor cell debris is internalized by PMNs and the tumor-cell material can be subsequently taken up from the immunomagnetically re-isolated PMNs by DC. Importantly, if human neutrophils had endocytosed bacteria, they were able to trigger the maturation program of the DC. Moreover, when mouse PMNs with E. coli in their interior are co-injected in the foot pad with DC, many DC loaded with fluorescent material from the PMNs reach draining lymph nodes. Using CT26 (H-2(d)) mouse tumor cells, it was observed that if tumor cells are intracellularly loaded with OVA protein and UV-irradiated, they become phagocytic prey of H-2(d) PMNs. If such PMNs, that cannot present antigens to OT-1 T cells, are immunomagnetically re-isolated and phagocytosed by H-2(b) DC, such DC productively cross-present OVA antigen determinants to OT-1 T cells. Cross-presentation to adoptively transferred OT-1 lymphocytes at draining lymph nodes also take place when OVA-loaded PMNs (H-2(d)) are coinjected in the footpad of mice with autologous DC (H-2(b)). In summary, our results indicate that antigens phagocytosed by short-lived PMNs can be in turn internalized and productively cross-presented by DC.
- Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocytedeficient mice reconstituted with human NK cells(Informa UK Limited, 2019) Berraondo, P. (Pedro); Zabaleta, A. (Aintzane); Fernández-Sendín, M. (Myriam); López-Botet, M. (Miguel); Perez-Ruiz, E. (Elisabeth); Rodriguez, I. (Inmaculada); Muntasell, A. (Aura); Oñate, C. (Carmen); Lopez, A. (Ascensión); Ochoa, M.C. (María Carmen); Alignani, D. (Diego); Melero, I. (Ignacio); Paiva, B. (Bruno); Perez, G. (Guiomar); Minute, L. (Luna); Fernandez-Sanmamed, M. (Miguel)Daratumumab is an anti-CD38 fully human IgG1 mAb approved for multiple myeloma treatment. One of the proposed mechanisms of action is the induction of antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells. NK cells acquire surface CD137 expression in the presence of solid-phase-attached daratumumab and when encountering a daratumumab-coated CD38+ tumor cell line. In this setting, addition of the agonist anti-CD137 mAb urelumab enhances NK-cell activation increasing CD25 expression and IFNɣ production. However, in vitro ADCC is not increased by the addition of urelumab both in 4h or 24h lasting experiments. To study urelumab-increased daratumumab-mediated ADCC activity in vivo, we set up a mouse model based on the intravenous administration of a luciferase-transfected multiple myeloma cell line of human origin, human NK cells and daratumumab to immuno-deficient NSG mice. In this model, intravenous administration of urelumab 24h after daratumumab delayed tumor growth and prolonged mice survival.
- A randomized phase II clinical trial of dendritic cell vaccination following complete resection of colon cancer liver metastasis(National Library of Medicine, 2018) Chopitea, A. (Ana); Alfaro, C. (Carlos); Rotellar, F. (Fernando); García-Rodríguez, J. (Javier); Perez-Gracia, J.L. (Jose Luis); Viudez, A. (Antonio); Rodriguez, I. (Inmaculada); Rodriguez-Ruiz, M.E. (María Esperanza); Lopez-Diaz-de-Cerio, A. (Ascensión); Castañón-Álvarez, E. (Eduardo); Oñate, C. (Carmen); Inoges, S. (Susana); Ponz-Sarvise, M. (Mariano); Melero, I. (Ignacio); Perez, G. (Guiomar); Resano, L. (Leyre); Vera, R. (Ruth)Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival –DFS-) 25.26 months, 95% CI 8. 74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32–18.88).