BRYAN ERIC STRAUSS
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
14 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 14
conferenceObject Potentiation of doxorubicin low-dose efficacy through its association with p19Arf/Interferon-beta immunotherapy: Combining two immunogenic cell death inducers for the treatment of cancer.(2018) SR., Ruan F. V. Medrano; SR., Samir A. Mendonca; SR., Aline H. Ribeiro; SR., Joao P. P. Catani; SR., Valker A. Feitosa; SR., Elaine G. Rodrigues; SR., Bryan E. Strauss- Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy(2017) MEDRANO, Ruan F. V.; HUNGER, Aline; MENDONCA, Samir Andrade; BARBUTO, Jose Alexandre M.; STRAUSS, Bryan E.During the last decades, the pleiotropic antitumor functions exerted by type I interferons (IFNs) have become universally acknowledged, especially their role in mediating interactions between the tumor and the immune system. Indeed, type I IFNs are now appreciated as a critical component of dendritic cell (DC) driven T cell responses to cancer. Here we focus on IFN-alpha and IFN-beta, and their antitumor effects, impact on immune responses and their use as therapeutic agents. IFN-alpha/beta share many properties, including activation of the JAK-STAT signaling pathway and induction of a variety of cellular phenotypes. For example, type I IFNs drive not only the high maturation status of DCs, but also have a direct impact in cytotoxic T lymphocytes, NK cell activation, induction of tumor cell death and inhibition of angiogenesis. A variety of stimuli, including some standard cancer treatments, promote the expression of endogenous IFN-alpha/beta, which then participates as a fundamental component of immunogenic cell death. Systemic treatment with recombinant protein has been used for the treatment of melanoma. The induction of endogenous IFN-alpha/beta has been tested, including stimulation through pattern recognition receptors. Gene therapies involving IFN-alpha/beta have also been described. Thus, harnessing type I IFNs as an effective tool for cancer therapy continues to be studied.
conferenceObject Combined p19Arf and Interferon-beta Gene Therapy: Evidence of Immune Response in Murine Models of Melanoma and Lung Carcinoma(2013) STRAUSS, Bryan E.; MEDRANO, Ruan Felipe V.; RIBEIRO, Aline H.; CATANI, Joao Paulo P.; MERKEL, Christian A.Background: Our previous work has included the development of viral vectors where transgene expression is controlled by the transcriptional functions of the p53 tumor suppressor protein. Since wild-type p53 is frequently maintained in melanoma, we propose that such vectors may provide an opportunity for interplay between endogenous and exogenous factors. Transfer of p19Arf, a functional partner of p53, should help activate endogenous p53, thus supporting both vector expression and killing of tumor cells. Interferon-beta (IFNβ) is known to activate the immune system, induce apoptosis and inhibit angiogenesis. Moreover, interactions of the p53/Arf and IFN pathways have been reported. Previously we have shown that combined, but not individual, transfer of p19Arf and IFNβ mediated by our p53-responsive Ad5 vector induced massive cell death of B16 (mouse melanoma) both in vitro and in vivo. Objective: Our current aims include revealing involvement of the immune system in response to gene transfer protocols utilizing p53-responsive Ad5 or AdRGD vectors. Methods/Results: B16 cells with forced expression of CAR were transduced ex vivo with the Ad5 vectors (called AdPG) and implanted subcutaneously in C57BL/6 mice. Seven days later, these same mice received a challenge with fresh B16 cells implanted s.c. in the contralateral flank. Transfer of IFNβ alone or in combination with p19Arf reduced tumor formation at the sites of the vaccination and challenge. However, the combined treatment resulted in smaller tumors with delayed progression and prolonged survival. In parallel, RGD-modified adenoviral vectors, AdRGDPG, were constructed and shown to increase viral tropism as well as provide the expected synergy between p19Arf and IFNβ in CAR-negative B16 cells. This new set of AdRGDPG vectors was used in a model of in situ gene therapy of Lewis Lung Carcinoma (LLC) where tumors were first established s.c. in C57BL/6 mice then treated in vivo with six rounds of viral transduction. Treatment with IFNβ alone or in combination with p19Arf was effective in retarding tumor progression. Strikingly, s.c. challenge tumors implanted in the contralateral flank were inhibited especially well only in the animals previously treated with the combination of p19Arf and IFNβ. Alternatively, LLC cells were implanted s.c. in Balb/c nude mice and treated in situ. In this case, we did not observe a reduction in tumor progression in any of the conditions, indicating the importance of the adaptive immune system for tumor inhibition in response to our gene transfer strategy. Conclusion: In mouse tumor cell lines that retain wild-type p53, treatment with the combination of p19 Arf and IFNβ appears to involve the immune system, induce immunological memory and may provide an advantage over mono-gene therapy.- Combined transfer of p19Arf and interferon-beta genes to mouse melanoma cells causes LC3B-and caspase-3-independent cell death and alters the expression of critical genes(2015) RIBEIRO, Aline H.; VALLE, Paulo R. Del; MEDRANO, Ruan F. V.; FERRARI, Daniel G.; ZANATTA, Daniela B.; STRAUSS, Bryan E.
- Intratumoral Immunization by p19Arf and Interferon-beta Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma(2016) CATANI, Joao Paulo Portela; MEDRANO, Ruan F. V.; HUNGER, Aline; VALLE, Paulo Del; ADJEMIAN, Sandy; ZANATTA, Daniela Bertolini; KROEMER, Guido; COSTANZI-STRAUSS, Eugenia; STRAUSS, Bryan E.Therapeutic strategies that act by eliciting and enhancing antitumor immunity have been clinically validated as an effective treatment modality but may benefit from the induction of both cell death and immune activation as primary stimuli. Using our AdRGD-PG adenovector platform, we show here for the first time that in situ gene transfer of p19Arf and interferon-beta (IFN beta) in the LLC1 mouse model of lung carcinoma acts as an immunotherapy. Although p19Arf is sufficient to induce cell death, only its pairing with IFN beta significantly inducedmarkers of immunogenic cell death. In situ gene therapy with IFN beta, either alone or in combination with p19Arf, could retard tumor progression, but only the combined treatment was associated with a protective immune response. Specifically in the case of combined intratumoral gene transfer, we identified 167 differentially expressed genes when usingmicroarray to evaluate tumors that were treated in vivo and confirmed the activation of CCL3, CXCL3, IL1 alpha, IL1 beta, CD274, and OSM, involved in immune response and chemotaxis. Histologic evaluation revealed significant tumor infiltration by neutrophils, whereas functional depletion of granulocytes ablated the antitumor effect of our approach. The association of in situ gene therapy with cisplatin resulted in synergistic elimination of tumor progression. In all, in situ gene transfer with p19Arf and IFN beta acts as an immunotherapy involving recruitment of neutrophils, a desirable but previously untested outcome, and this approach may be allied with chemotherapy, thus providing significant antitumor activity and warranting further development for the treatment of lung carcinoma.
- Vaccination using melanoma cells treated with p19arf and interferon beta gene transfer in a mouse model: a novel combination for cancer immunotherapy(2016) MEDRANO, Ruan Felipe Vieira; CATANI, Joao Paulo Portela; RIBEIRO, Aline Hunger; TOMAZ, Samanta Lopes; MERKEL, Christian A.; COSTANZI-STRAUSS, Eugenia; STRAUSS, Bryan E.Previously, we combined p19(Arf) (Cdkn2a, tumor suppressor protein) and interferon beta (IFN-beta, immunomodulatory cytokine) gene transfer in order to enhance cell death in a murine model of melanoma. Here, we present evidence of the immune response induced when B16 cells succumbing to death due to treatment with p19(Arf) and IFN-beta are applied in vaccine models. Use of dying cells for prophylactic vaccination was investigated, identifying conditions for tumor-free survival. After combined p19(Arf) and IFN-beta treatment, we observed immune rejection at the vaccine site in immune competent and nude mice with normal NK activity, but not in NOD-SCID and dexamethasone immunosuppressed mice (NK deficient). Combined treatment induced IL-15, ULBP1, FAS/APO1 and KILLER/DR5 expression, providing a mechanism for NK activation. Prophylactic vaccination protected against tumor challenge, where markedly delayed progression and leukocyte infiltration were observed. Analysis of primed lymphocytes revealed secretion of TH1-related cytokines and depletion protocols showed that both CD4(+) and CD8(+) T lymphocytes are necessary for immune protection. However, application of this prophylactic vaccine where cells were treated either with IFN-beta alone or combined with p19(Arf) conferred similar immune protection and cytokine activation, yet only the combination was associated with increased overall survival. In a therapeutic vaccine protocol, only the combination was associated with reduced tumor progression. Our results indicate that by harnessing cell death in an immunogenic context, our p19(Arf) and IFN-beta combination offers a clear advantage when both genes are included in the vaccine and warrants further development as a novel immunotherapy for melanoma.
- Harnessing combined p19Arf and interferon-beta gene transfer as an inducer of immunogenic cell death and mediator of cancer immunotherapy(2017) HUNGER, Aline; MEDRANO, Ruan F. V.; STRAUSS, Bryan E.
- Induction of Oxidants Distinguishes Susceptibility of Prostate Carcinoma Cell Lines to p53 Gene Transfer Mediated by an Improved Adenoviral Vector(2017) TAMURA, Rodrigo Esaki; HUNGER, Aline; FERNANDES, Denise C.; LAURINDO, Francisco R.; COSTANZI-STRAUSS, Eugenia; STRAUSS, Bryan E.Previously, the authors developed an adenoviral vector, Ad-PG, where transgene expression is regulated by a p53-responsive promoter. When used to transfer the p53 cDNA, a positive feedback mechanism is established. In the present study, a critical comparison is performed between Ad-PGp53 and AdRGD-PGp53, where the RGD motif was incorporated in the adenoviral fiber protein. AdRGD-PGp53 provided superior transgene expression levels and resulted in the killing of prostate carcinoma cell lines DU145 and PC3. In vitro, this effect was associated with increased production of cytoplasmic and mitochondrial oxidants, DNA damage as revealed by detection of phosphorylated H2AX, as well as cell death consistent with apoptosis. Differential gene expression of key mediators of reactive oxygen species pathways was also observed. Specifically, it was noted that induction of known p53-target genes Sestrin2 and PIG3, as well as a novel target, NOX1, occurred in PC3 cells only when transduced with the improved vector, AdRGD-PGp53. The participation of NOX1 was confirmed upon its inhibition using a specific peptide, resulting in reduced cell death. In situ gene therapy also resulted in significantly improved inhibition of tumor progression consistent with oxidant-induced DNA damage only when treated with the novel AdRGD-PGp53 vector. The study shows that the improved adenovirus overcomes limitations associated with other p53-expressing vectors and induces oxidant-mediating killing, thus supporting its further development for cancer gene therapy.
conferenceObject Cancer Immunotherapy Mediated by Combined p19Arf and Interferon-Beta Gene Transfer: Evidence from Vaccine and In Situ Gene Therapy Models(2017) STRAUSS, Bryan E.; MEDRANO, Ruan F. V.; CATANI, Joao Paulo P.; HUNGER, Aline- Uncovering the immunotherapeutic cycle initiated by p19Arf and interferon-beta gene transfer to cancer cells: An inducer of immunogenic cell death(2017) MEDRANO, Ruan F. V.; HUNGER, Aline; CATANI, Joao P. P.; STRAUSS, Bryan E.Simultaneous reestablishment of p53/p19(Arf) and interferon-beta pathways in melanoma cells culminates in a cell death process that displays features of necroptosis along with the release of immunogenic cell death molecules and unleashes an antitumor immune response mediated by natural killer cells, neutrophils as well as CD4(+) and CD8(+) T lymphocytes.