Hervas-Stubbs, S. (Sandra)
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- Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice(2011) Berraondo, P. (Pedro); González-Aseguinolaza, G. (Gloria); Mancheño, U. (Uxua); Alzuguren, P. (Pilar); Hervas-Stubbs, S. (Sandra); Crettaz, J. (Julien); Prieto, J. (Jesús); Medina-Echeverz, J. (José); Hernandez-Alcoceba, R. (Rubén); Gonzalez-Aparicio, M. (Manuela); Mauleon, I. (Itsaso)BACKGROUND AND AIMS: New options are needed for the management and prevention of colorectal cancer liver metastases. Interleukin 12 (IL-12) is an immunostimulatory cytokine with proven antitumour effect in animal models. Despite evidence indicating its biological effect in humans, neither the recombinant protein nor gene therapy vectors expressing IL-12 have shown a relevant benefit in patients with cancer. OBJECTIVE: To develop a new approach to overcome the difficulties in obtaining a suitable expression pattern and the immunosuppressive milieu in the tumours which contribute to this poor performance. METHODS: A high-capacity ('gutless') adenoviral vector carrying a liver-specific, mifepristone (Mif)-inducible system for the expression of IL-12 (HC-Ad/RUmIL-12) was used in combination with chemotherapy. Tumours were established in the liver of C57BL/6 mice by inoculation of MC38 colon cancer cells. RESULTS: Intrahepatic injection of HC-Ad/RUmIL-12 and tailored induction regimens allowed the maintenance of safe and efficient levels of IL-12 in vivo. An individualised, stepwise increase in the dose of Mif (125-4000 μg/kg) was needed to compensate for the progressive but transient downregulation of the inducible system. Repeated cycles of Mif induction (every 24 h for 10 days) were needed for optimal tumour eradication. However, complete protection against tumour rechallenge was seen in < 25% of the animals. The administration of oxaliplatin (5 mg/kg intraperitoneally) 3 days before starting the induction regimen achieved efficient elimination of liver metastases with a single cycle of IL-12 induction, and improved protection against tumour rechallenge. This was associated with a shift in the tumour microenvironment towards a more pro-immunogenic phenotype, with an increase in the CD8+/T regulatory cell ratio and a reduction in myeloid-derived suppressor cells. These effects were not seen with 5-fluorouracil, irinotecan or gemcitabine.
- Immunostimulatory monoclonal antibodies for cancer therapy(Nature Publishing Group, 2007) Hervas-Stubbs, S. (Sandra); Glennie, M. (Martín); Melero, I. (Ignacio); Pardoll, D.M. (Drew M.); Chen, L. (Lieping)Increasing immune responses with immunostimulatory monoclonal antibodies (mAbs) directed to immune-receptor molecules is a new and exciting strategy in cancer therapy. This expanding class of agents functions on crucial receptors, either antagonizing those that suppress immune responses or activating others that amplify immune responses. Complications such as autoimmunity and systemic inflammation are problematic side effects associated with these agents. However, promising synergy has been observed in preclinical models using combinations of immunostimulatory antibodies and other immunotherapy strategies or conventional cancer therapies. Importantly, mAbs of this type have now entered clinical trials with encouraging initial results.
- Protection against woodchuck hepatitis virus (WHV) infection by gene gun coimmunization with WHV core and interleukin-12(American Society for Microbiology, 2001) Berraondo, P. (Pedro); Vales, A. (África); Borras-Cuesta, F. (Francisco); Sanchez-de-la-Rosa, R. (R.); Raquel; Hervas-Stubbs, S. (Sandra); Prieto, J. (Jesús); Blanco-Urgoiti, B. (Begoña); Ruiz, J. (Juan); Lasarte, J.J. (Juan José)Woodchuck hepatitis virus (WHV) and hepatitis B virus (HBV) are closely similar with respect to genomic organization, host antiviral responses, and pathobiology of the infection. T-cell immunity against viral nucleocapsid (HBcAg or WHcAg) has been shown to play a critical role in viral clearance and protection against infection. Here we show that vaccination of healthy woodchucks by gene gun bombardment with a plasmid coding for WHcAg (pCw) stimulates proliferation of WHcAg-specific T cells but that these cells do not produce significant levels of gamma interferon (IFN-gamma) upon antigen stimulation. In addition, animals vaccinated with pCw alone were not protected against WHV inoculation. In order to induce a Th1 cytokine response, another group of woodchucks was immunized with pCw together with another plasmid coding for woodchuck interleukin-12 (IL-12). These animals exhibited WHcAg-specific T-cell proliferation with high IFN-gamma production and were protected against challenge with WHV, showing no viremia or low-level transient viremia after WHV inoculation. In conclusion, gene gun immunization with WHV core generates a non-Th1 type of response which does not protect against experimental infection. However, steering the immune response to a Th1 cytokine profile by IL-12 coadministration achieves protective immunity. These data demonstrate a crucial role of Th1 responses in the control of hepadnavirus replication and suggest new approaches to inducing protection against HBV infection.
- Evaluation of monocytes as carriers for armed oncolytic adenoviruses in murine and Syrian hamster models of cancer(Mary Ann Liebert, 2012) Garcia-Aragoncillo, E. (Eva); Quetglas, J.I. (José Ignacio); Ortiz-de-Solorzano, C. (Carlos); Hervas-Stubbs, S. (Sandra); Prieto, J. (Jesús); Bortolanza, S. (Sergia); Hernandez-Alcoceba, R. (Rubén); Benavides, C. (Carolina); Buñuales, M. (María); RaquelReplication-competent (oncolytic) adenoviruses (OAV) can be adapted as vectors for the delivery of therapeutic genes, with the aim of extending the antitumor effect beyond direct cytolysis. Transgene expression using these vectors is usually intense but short-lived, and repeated administrations are hampered by the rapid appearance of neutralizing antibodies (NAbs). We have studied the performance of monocytes as cell carriers to improve transgene expression in cancer models established in athymic mice and immunocompetent Syrian hamsters. Human and hamster monocytic cell lines (MonoMac6 and HM-1, respectively) were loaded with replication-competent adenovirus-expressing luciferase. Intravenous administration of these cells caused a modest increase in transgene expression in tumor xenografts, but this effect was virtually lost in hamsters. In contrast, intratumoral administration of HM-1 cells allowed repeated cycles of expression and achieved partial protection from NAbs in preimmunized hamsters bearing pancreatic tumors. To explore the therapeutic potential of this approach, HM-1 cells were loaded with a hypoxia-inducible OAV expressing the immunostimulatory cytokine interleukin-12 (IL-12). Three cycles of treatment achieved a significant antitumor effect in the hamster model, and transgene expression was detected following each administration, in contrast with the rapid neutralization of the free virus. We propose monocytes as carriers for multiple intratumoral administrations of armed OAVs.
- Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes(Cancer Research UK, 2009) Dubrot, J. (Juan); Alfaro, C. (Carlos); Solano, S. (Sarai); Perez-Gracia, J.L. (Jose Luis); Lopez-Picazo, J.M. (José M.); Gonzalez-Hernandez, A. (Alvaro); Gurpide, A. (Alfonso); Hervas-Stubbs, S. (Sandra); Erro, L. (Lorena); Melero, I. (Ignacio); Palazon, A. (Asís); Suarez, N. (Natalia); Grande-Pulido, E. (E.)Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.
- International symposium on CTL and immunostimulation, Pamplona (Spain), October 26th and 27th 2010(Springer Verlag, 2011) Berraondo, P. (Pedro); Martinez-Forero, I. (Iván); Melcher, A. (Alan); Hervas-Stubbs, S. (Sandra); Ochoa, M.C. (María Carmen); Melero, I. (Ignacio); Palazon, A. (Asís); Sarobe, P. (Pablo)
- Serum levels of S-100 protein are directly proportional to the size, number, thickness and degree of cellularity of congenital melanocytic nevi(Elsevier, 2023) López-Gutiérrez, J.C. (Juan Carlos); Tomás-Velázquez, A. (Alejandra); Andrés, E.M. (Eva M.); Reyes, M. (Miguel); Salgado, C.M. (Claudia M.); Ceballos-Rodríguez, C. (Carmen); Triana, P. (Paloma); Hervas-Stubbs, S. (Sandra); Reina, G. (Gabriel); Andrea, C.E. (Carlos Eduardo) de; Basu, D. (Dipanjan); Redondo-Bellón, P. (Pedro)To the Editor: Some patients with congenital melanocytic nevi (CMN) present progressive growth and thickening, extracutaneous involvement (neurocutaneous melanocytosis, NCM) or neoplastic transformation (melanoma); and others remain stable or even regress. There are no markers to assess progression or follow-up. Recently, we found S-100, a protein which acts on cell differentiation and proliferation, elevated in CMN.1 S-100 is a ligand of the RAGE pathway (related to the MAPK-pathway), and low serum levels of soluble-RAGE were related to poor survival in melanoma.2 Also SOX10, expressed in melanocytes with high specificity, is useful in detection, prognosis and treatment assessment of melanoma.3 We explored if S-100, RAGE and SOX10 serum levels vary in children’s CMN and assessed clinical or pathological correlations.
- Midbrain microglia mediate a specific immunosuppressive response under inflammatory conditions(Springer Science and Business Media LLC, 2019) Vilas, A. (Amaia); Abellanas-Sánchez, M.A. (Miguel Ángel); San-Martín-Uriz, P. (Patxi); Zamarbide-González, M. (Marta); Aymerich-Soler, M.S. (María Soledad); Basurco, L. (Leyre); Hervas-Stubbs, S. (Sandra); Garcia-Granero, M. (Marta); Mengual, E. (Elisa); Clavero, P. (P.); Luquin, E. (Esther)Background: Inflammation is a critical process for the progression of neuronal death in neurodegenerative disorders. Microglia play a central role in neuroinflammation and may affect neuron vulnerability. Next generation sequencing has shown the molecular heterogeneity of microglial cells; however, the variability in their response to pathological inputs remains unknown. Methods: To determine the effect of an inflammatory stimulus on microglial cells, lipopolysaccharide (LPS) was administered peripherally to mice and the inflammatory status of the cortex, hippocampus, midbrain, and striatum was assessed. Microglial activation and interaction with the immune system were analyzed in single cell suspensions obtained from the different brain regions by fluorescence-activated cell sorting, next generation RNA sequencing, real-time PCR, and immunohistochemical techniques. Antigen-presenting properties of microglia were evaluated by the ability of isolated cells to induce a clonal expansion of CD4+ T cells purified from OT-II transgenic mice. Results: Under steady-state conditions, the midbrain presented a high immune-alert state characterized by the presence of two unique microglial subpopulations, one expressing the major histocompatibility complex class II (MHC-II) and acting as antigen-presenting cells and another expressing the toll-like receptor 4 (TLR4), and by the presence of a higher proportion of infiltrating CD4+ T cells. This state was not detected in the cortex, hippocampus, or striatum. Systemic LPS administration induced a general increase in classic pro-inflammatory cytokines, in coinhibitory programmed death ligand 1 (PD-L1), and in cytotoxic T lymphocyte antigen 4 (CTLA-4) receptors, as well as a decrease in infiltrating effector T cells in all brain regions. Interestingly, a specific immune-suppressive response was observed in the midbrain which was characterized by the downregulation of MHC-II microglial expression, the upregulation of the anti-inflammatory cytokines IL10 and TGFβ, and the increase in infiltrating regulatory T cells. Conclusions: These data show that the midbrain presents a high immune-alert state under steady-state conditions that elicits a specific immune-suppressive response when exposed to an inflammatory stimulus. This specific inflammatory tone and response may have an impact in neuronal viability
- Carcinoma-derived interleukin-8 disorients dendritic cell migration without impairing T-cell stimulation(Public Library of Science, 2011) Dubrot, J. (Juan); Martinez-Forero, I. (Iván); Alfaro, C. (Carlos); Solano, S. (Sarai); Perez-Gracia, J.L. (Jose Luis); Rouzaut, A. (Ana); Bolaños, E. (Elixabet); Gonzalez-Hernandez, A. (Alvaro); Gurpide, A. (Alfonso); Hervas-Stubbs, S. (Sandra); Erro, L. (Lorena); Melero, I. (Ignacio); Palazon, A. (Asís); Suarez, N. (Natalia); Feijoo, E. (Esperanza)BACKGROUND: Interleukin-8 (IL-8, CXCL8) is readily produced by human malignant cells. Dendritic cells (DC) both produce IL-8 and express the IL-8 functional receptors CXCR1 and CXCR2. Most human colon carcinomas produce IL-8. IL-8 importance in malignancies has been ascribed to angiogenesis promotion. PRINCIPAL FINDINGS: IL-8 effects on human monocyte-derived DC biology were explored upon DC exposure to recombinant IL-8 and with the help of an IL-8 neutralizing mAb. In vivo experiments were performed in immunodeficient mice xenografted with IL-8-producing human colon carcinomas and comparatively with cell lines that do not produce IL-8. Allogenic T lymphocyte stimulation by DC was explored under the influence of IL-8. DC and neutrophil chemotaxis were measured by transwell-migration assays. Sera from tumor-xenografted mice contained increasing concentrations of IL-8 as the tumors progress. IL-8 production by carcinoma cells can be modulated by low doses of cyclophosphamide at the transcription level. If human DC are injected into HT29 or CaCo2 xenografted tumors, DC are retained intratumorally in an IL-8-dependent fashion. However, IL-8 did not modify the ability of DC to stimulate T cells. Interestingly, pre-exposure of DC to IL-8 desensitizes such cells for IL-8-mediated in vitro or in vivo chemoattraction. Thereby DC become disoriented to subsequently follow IL-8 chemotactic gradients towards malignant or inflamed tissue. CONCLUSIONS: IL-8 as produced by carcinoma cells changes DC migration cues, without directly interfering with DC-mediated T-cell stimulation.
- Clinical development of combination strategies in immunotherapy: are we ready for more than one investigational product in an early clinical trial?(Future Medicine, 2009) Berraondo, P. (Pedro); Martinez-Forero, I. (Iván); Alfaro, C. (Carlos); Perez-Gracia, J.L. (Jose Luis); Sangro, B. (Bruno); Gurpide, A. (Alfonso); Hervas-Stubbs, S. (Sandra); Ochoa, M.C. (María Carmen); Melero, J.A. (José A.); Melero, I. (Ignacio); Suarez, N. (Natalia)Stimulating the innate and adaptive immunity against cancer necessitates the tricking of a system evolved to fight microbial pathogens and directing its activity towards transformed self-tissue. Efficacious interventions to start and sustain the response will probably require a number of agents to tamper simultaneously or sequentially with several immune mechanisms. Although master switches controlling various functions may exist, the goal of a curative immune response will probably demand the combined actions of several therapeutic components. Synergy occurs when drugs interact in ways that enhance or magnify one or more effects or side effects. In cancer immunotherapy, two agents that have minor or no therapeutic effects as single agents can be powerful when combined. Mouse experimentation provides multiple examples of synergistic combinations. Elements to be combined include chiefly: tumor vaccines, adoptive T-cell therapies, cytokines, costimulatory molecules, molecular deactivation of immunosuppressive or tolerogenic pathways and immunostimulatory monoclonal antibodies. These novel therapies, even as single agents, are extremely complex products to be developed owing to the associated biomolecules, cell therapies or gene therapies. At present, drug-development programs are run individually for each immunotherapeutic agent and combinations are considered only at a later stage in clinical development, even in the absence of formal compulsory regulations to prevent clinical trials with combinations. As a result, instead of the search for maximal efficacy, ease of combination with standard treatments, intellectual property management, regulations and business-based decisions often guide the way. Even though the maximal effort must be made in order to prevent adverse effects in patients, it seems reasonable that combination pilot trials should be performed at an early stage, following safe completion of Phase I trials. These trials should be performed based on evidence for synergy in animal models and be simplified in terms of regulatory requirements. Such 'short-cut' combination immunotherapy trials can bring much needed efficacy earlier to the bedside.