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
8 resultados
Resultados de Busca
Agora exibindo 1 - 8 de 8
- Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer(2018) STRAUSS, Bryan E.; SILVA, Gissele Rolemberg Oliveira; VIEIRA, Igor de Luna; CERQUEIRA, Otto Luiz Dutra; VALLE, Paulo Roberto Del; MEDRANO, Ruan Felipe Vieira; MENDONCA, Samir AndradeWhile cancer immunotherapy has gained much deserved attention in recent years, many areas regarding the optimization of such modalities remain unexplored, including the development of novel approaches and the strategic combination of therapies that target multiple aspects of the cancer-immunity cycle. Our own work involves the use of gene transfer technology to promote cell death and immune stimulation. Such immunogenic cell death, mediated by the combined transfer of the alternate reading frame (p14ARF in humans and p19Arf in mice) and the interferon-beta cDNA in our case, was shown to promote an antitumor immune response in mouse models of melanoma and lung carcinoma. With these encouraging results, we are now setting out on the road toward translational and preclinical development of our novel immunotherapeutic approach. Here, we outline the perspectives and challenges that we face, including the use of human tumor and immune cells to verify the response seen in mouse models and the incorporation of clinically relevant models, such as patient-derived xenografts and spontaneous tumors in animals. In addition, we seek to combine our immunotherapeutic approach with other treatments, such as chemotherapy or checkpoint blockade, with the goal of reducing dosage and increasing efficacy. The success of any translational research requires the cooperation of a multidisciplinary team of professionals involved in laboratory and clinical research, a relationship that is fostered at the Cancer Institute of Sao Paulo.
conferenceObject ONCOLYSIS MEDIATED BY INFB AND ARF GENE TRANSFER ACTIVATES KEY COMPONENTS OF THE IMMUNE SYSTEM(2021) CERQUEIRA, O. L. D.; STRAUSS, B. E.conferenceObject Induction of cell death in human melanoma cell lines by the combination of p14ARF plus interferon-beta gene transfer(2019) MENDONCA, S. A.; CERQUEIRA, O. L.; STRAUSS, B. E.- Combined p14ARF and Interferon-beta Gene Transfer to the Human Melanoma Cell Line SK-MEL-147 Promotes Oncolysis and Immune Activation(2020) CERQUEIRA, Otto Luiz Dutra; CLAVIJO-SALOMON, Maria Alejandra; CARDOSO, Elaine Cristina; TORTELLI JUNIOR, Tharcisio Citrangulo; MENDONCA, Samir Andrade; BARBUTO, Jose Alexandre M.; STRAUSS, Bryan E.Immune evasion is an important cancer hallmark and the understanding of its mechanisms has generated successful therapeutic approaches. Induction of immunogenic cell death (ICD) is expected to attract immune cell populations that promote innate and adaptive immune responses. Here, we present a critical advance for our adenovirus-mediated gene therapy approach, where the combined p14ARF and human interferon-beta (IFN beta) gene transfer to human melanoma cells led to oncolysis, ICD and subsequent activation of immune cells. Our results indicate that IFN beta alone or in combination with p14ARF was able to induce massive cell death in the human melanoma cell line SK-MEL-147, though caspase 3/7 activation was not essential. In situ gene therapy of s.c. SK-MEL-147 tumors in Nod-Scid mice revealed inhibition of tumor growth and increased survival in response to IFN beta alone or in combination with p14ARF. Emission of critical markers of ICD (exposition of calreticulin, secretion of ATP and IFN beta) was stronger when cells were treated with combined p14ARF and IFN beta gene transfer. Co-culture of previously transduced SK-MEL-147 cells with monocyte-derived dendritic cells (Mo-DCs) derived from healthy donors resulted in increased levels of activation markers HLA-DR, CD80, and CD86. Activated Mo-DCs were able to prime autologous and allogeneic T cells, resulting in increased secretion of IFN gamma, TNF-alpha, and IL-10. Preliminary data showed that T cells primed by Mo-DCs activated with p14ARF+IFN beta-transduced SK-MEL-147 cells were able to induce the loss of viability of fresh non-transduced SK-MEL-147 cells, suggesting the induction of a specific cytotoxic population that recognized and killed SK-MEL-147 cells. Collectively, our results indicate that p14ARF and IFN beta delivered by our adenoviral system induced oncolysis in human melanoma cells accompanied by adaptive immune response activation and regulation.
- Response of human melanoma cell lines to interferon-beta gene transfer mediated by a modified adenoviral vector(2020) DAVID, Taynah I. P.; CERQUEIRA, Otto L. D.; LANA, Marlous G.; V, Ruan F. Medrano; HUNGER, Aline; STRAUSS, Bryan E.Since melanomas often retain wild type p53, we developed an adenoviral vector, AdRGD-PG, which provides robust transduction and transgene expression in response to p53. Previously, this vector was used for interferon-beta gene transfer in mouse models of melanoma, resulting in control of tumor progression, but limited cell killing. Here, the AdRGD-PG-hIFN beta vector encoding the human interferon-beta cDNA (hIFN beta) was used to transduce human melanoma cell lines SK-MEL-05 and SK-MEL-147 (both wild type p53). In vitro, cell death was induced in more than 80% of the cells and correlated with elevated annexinV staining and caspase 3/7 activity. Treatment with hIFN beta promoted cell killing in neighboring, non-transduced cells, thus revealing a bystander effect. In situ gene therapy resulted in complete inhibition of tumor progression for SK-MEL-147 when using nude mice with no evidence of hepatotoxicity. However, the response in Nod-Scid mice was less robust. For SK-MEL-05, tumor inhibition was similar in nude and Nod-Scid mice and was less efficient than seen for SK-MEL-147, indicating both cell type and host specific responses. The AdRGD-PG-hIFN beta vector provides extensive killing of human melanoma cells in vitro and a potent anti-tumor effect in vivo. This study provides a critical advance in the development of our melanoma gene therapy approach.
- Perspectives for Combining Viral Oncolysis With Additional Immunotherapies for the Treatment of Melanoma(2022) CERQUEIRA, Otto Luiz Dutra; ANTUNES, Fernanda; ASSIS, Nadine G.; CARDOSO, Elaine C.; CLAVIJO-SALOMON, Maria A.; DOMINGUES, Ana C.; TESSAROLLO, Nayara G.; STRAUSS, Bryan E.Melanoma is the deadliest type of skin cancer with steadily increasing incidence worldwide during the last few decades. In addition to its tumor associated antigens (TAAs), melanoma has a high mutation rate compared to other tumors, which promotes the appearance of tumor specific antigens (TSAs) as well as increased lymphocytic infiltration, inviting the use of therapeutic tools that evoke new or restore pre-existing immune responses. Innovative therapeutic proposals, such as immune checkpoint inhibitors (ICIs), have emerged as effective options for melanoma. However, a significant portion of these patients relapse and become refractory to treatment. Likewise, strategies using viral vectors, replicative or not, have garnered confidence and approval by different regulatory agencies around the world. It is possible that further success of immune therapies against melanoma will come from synergistic combinations of different approaches. In this review we outline molecular features inherent to melanoma and how this supports the use of viral oncolysis and immunotherapies when used as monotherapies or in combination.
- Induction of Immune-Stimulating Factors and Oncolysis Upon p14(ARF) Gene Transfer in Melanoma Cell Lines(2023) MENDONCA, Samir Andrade; ANTUNES, Fernanda; CERQUEIRA, Otto L. D.; VALLE, Paulo Roberto Del; HUNGER, Aline; OLIVEIRA, Percillia V. S. de; BRITO, Barbara; COSTANZI-STRAUSS, Eugenia; STRAUSS, Bryan E.Together with an anti-tumor immune response, oncolysis using a recombinant viral vector promises to eliminate cancer cells by both gene transfer and host-mediated functions. In this study we explore oncolysis induced by nonreplicating adenoviral vectors used for p14(ARF) and interferon-beta (hIFN beta) gene transfer in human melanoma cell lines, revealing an unexpected role for p14(ARF) in promoting cellular responses predictive of immune stimulation. Oncolysis was confirmed when UACC-62 (p53 wild-type) cells succumbed upon p14(ARF) gene transfer in vitro, whereas SK-Mel-29 (p53-mutant) benefitted from its combination with hIFN beta. In the case of UACC-62, in situ gene therapy in nude mice yielded reduced tumor progression in response to the p14(ARF) and hIFN beta combination. Potential for immune stimulation was revealed where p14(ARF) gene transfer in vitro was sufficient to induce emission of immunogenic cell death factors in UACC-62 and upregulate pro-immune genes, including IRF1, IRF7, IRF9, ISG15, TAP-1, and B2M. In SK-Mel-29, p14(ARF) gene transfer induced a subset of these factors. hIFN beta was, as expected, sufficient to induce these immune-stimulating genes in both cell lines. This work is a significant advancement for our melanoma gene therapy strategy because we revealed not only the induction of oncolysis, but also the potential contribution of p14(ARF) to immune stimulation.
- Nonreplicating Adenoviral Vectors: Improving Tropism and Delivery of Cancer Gene Therapy(2021) TESSAROLLO, Nayara Gusmao; DOMINGUES, Ana Carolina M.; ANTUNES, Fernanda; LUZ, Jean Carlos dos Santos da; RODRIGUES, Otavio Augusto; CERQUEIRA, Otto Luiz Dutra; STRAUSS, Bryan E.Simple Summary The treatment of cancer has progressed greatly with the advent of immunotherapy and gene therapy, including the use of nonreplicating adenoviral vectors to deliver genes with antitumor activity for cancer gene therapy. Even so, the successful application of these vectors may benefit from modifications in their design, including their molecular structure, so that specificity for the target cell is increased and off-target effects are minimized. With such improvements, we may find new opportunities for systemic administration of adenoviral vectors as well as the delivery of strategic antigen targets of an antitumor immune response. We propose that the improvement of nonreplicating adenoviral vectors will allow them to continue to hold a key position in cancer gene therapy and immunotherapy. Recent preclinical and clinical studies have used viral vectors in gene therapy research, especially nonreplicating adenovirus encoding strategic therapeutic genes for cancer treatment. Adenoviruses were the first DNA viruses to go into therapeutic development, mainly due to well-known biological features: stability in vivo, ease of manufacture, and efficient gene delivery to dividing and nondividing cells. However, there are some limitations for gene therapy using adenoviral vectors, such as nonspecific transduction of normal cells and liver sequestration and neutralization by antibodies, especially when administered systemically. On the other hand, adenoviral vectors are amenable to strategies for the modification of their biological structures, including genetic manipulation of viral proteins, pseudotyping, and conjugation with polymers or biological membranes. Such modifications provide greater specificity to the target cell and better safety in systemic administration; thus, a reduction of antiviral host responses would favor the use of adenoviral vectors in cancer immunotherapy. In this review, we describe the structural and molecular features of nonreplicating adenoviral vectors, the current limitations to their use, and strategies to modify adenoviral tropism, highlighting the approaches that may allow for the systemic administration of gene therapy.