JOAO PAULO PORTELA CATANI
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Anti-tumor Effect of P19Arf and Interferon-beta Gene Transference to Mouse Melanoma and Mouse Lung Carcinoma Cells is Revealed by a Strong Bystander Activity and a Potential Immune Response(2012) RIBEIRO, A. H.; MEDRANO, R. F. V.; CATANI, J. P. P.; STRAUSS, B. E.Introduction: Two hallmarks of tumor progression are resistance to cell death and lack of an effective anti-tumor immune response. Loss of p53 function, by genetic mutation or alterations in its pathway, such as p19Arf loss and/or mdm2 over-expression, inhibits one of the primary coordinators of cell death. Interferon-beta (IFN), a stimulator of the immune response with anti-neoplastic functions, is also frequently lost in some tumor types. We propose that p19Arf and IFN gene transfer would be an effective strategy, especially in wild-type p53 tumor cells, since cell death and immune activation would be combined to combat the tumor at primary treatment site and metastasis. Material and Methods: Recombinant adenoviral vectors with RGD-modified fiber (rAdRGD) and a p53-responsive promoter (PG) were constructed containing genes of p19Arf, IFN or the combination of both. Evaluation of in vitro antiproliferative effect of transgenes in B16F10 cells (B16, mouse melanoma, p53 wt) was done by annexin/PI staining and MTT assays. Bystander effect was revealed by cell cycle analysis of populations transduced with different proportions of the viruses. Antitumor effect in vivo was observed by treatment of established LLC1 tumors (mouse lung carcinoma, p53 wt) with intratumoral injection of rAdRGD in C57BL/6 mice. Involvement of immune response was revealed by second tumor challenge at contralateral flank of mice with a developed and treated first tumor. Results and Discussion: Cell death was resulted from the p19Arf and IFN combined transference (74% subG0), yet single gene transfer yielded only half the number of subG0 cells. A similar result was seen by measurement of cell viability with MTT. Evidence on a bystander effect was revealed when approximately 50% subG0 cells were observed, even though only 10% of the cells had been transduced with IFN. In a population of cells transduced with p19Arf, when 10% of them also expressed IFN, the number of subG0 cells increased to 68%, compared to transduction of p19Arf alone, which results in 45% subG0 cells. This indicates that p19Arf can sensitize cells to death by IFN bystander effect. In vivo assays with the LLC1 model have shown that in situ gene therapy of p19Arf and IFN combination was more effective to inhibit tumor progression and increase survival than application of a single gene. These animals were then challenged with the implantation of a second tumor, revealing greater retardation of growth at the secondary tumor site in mice treated with the combined gene therapy at the primary tumor locus as compared to animals that received single gene treatment. Conclusion: The use of p53-responsive vectors to express p19Arf and IFN represents a potential strategy for melanoma and lung carcinoma tumor suppression. We have shown that complementation of the p53/Arf and interferon pathways in the primary tumor may generate a strong bystander effect as well as immune stimulation.- Use of p19Arf/interferon-beta immunotherapy in association with chemotherapy permits reduced drug dosage and avoids cardiotoxicity associated with doxorubicin(2019) STRAUSS, Bryan E.; MEDRANO, Ruan F. V.; TAMURA, Rodrigo; MENDONCA, Samir A.; FEITOSA, Valker A.; DARIOLLI, Rafael; SALLES, Thiago A.; HUNGER, Aline; CATANI, Joao P. P.; RODRIGUES, Elaine G.
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. StraussconferenceObject 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.- Near future of tumor immunology: Anticipating resistance mechanisms to immunotherapies, a big challenge for clinical trials(2017) CATANI, Joao Paulo Portela; RIECHELMANN, Rachel P.; ADJEMIAN, Sandy; STRAUSS, Bryan E.The success of immunotherapies brings hope for the future of cancer treatment. Even so, we are faced with a new challenge, that of understanding which patients will respond initially and, possibly, develop resistance. The examination of the immune profile, especially approaches related to the immunoscore, may foretell which tumors will have a positive initial response. Ideally, the mutation load would also be analyzed, helping to reveal tumor associated antigens that are predictive of an effective cytolytic attack. However, the response may be hindered by changes induced in the tumor and its microenvironment during treatment, perhaps stemming from the therapy itself. To monitor such alterations, we suggest that minimally invasive approaches should be explored, such as the analysis of circulating tumor DNA. When testing new drugs, the data collected from each patient would initially represent an N of 1 clinical trial that could then be deposited in large databases and mined retrospectively for trends and correlations between genetic alterations and response to therapy. We expect that the investment in personalized approaches that couple molecular analysis during clinical trials will yield critical data that, in the future, may be used to predict the outcome of novel immunotherapies.
- 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.
- CCL2/CCR2-Dependent Recruitment of Functional AntigenPresenting Cells into Tumors upon Chemotherapy(2014) MA, Yuting; MATTAROLLO, Stephen R.; ADJEMIAN, Sandy; YANG, Heng; AYMERIC, Laetitia; HANNANI, Dalil; CATANI, Joao Paulo Portela; DURET, Helene; TENG, Michele W. L.; KEPP, Oliver; WANG, Yidan; SISTIGU, Antonella; SCHULTZE, Joachim L.; STOLL, Gautier; GALLUZZI, Lorenzo; ZITVOGEL, Laurence; SMYTH, Mark J.; KROEMER, GuidoThe therapeutic efficacy of anthracyclines relies, at least partially, on the induction of a dendritic cell-and T-lymphocyte-dependent anticancer immune response. Here, we show that anthracycline-based chemotherapy promotes the recruitment of functional CD11b(+)CD11c(+)Ly6C(high)Ly6G(-)MHCII(+) dendritic cell-like antigenpresenting cells (APC) into the tumor bed, but not into lymphoid organs. Accordingly, draining lymph nodes turned out to be dispensable for the proliferation of tumor antigen-specific T cells within neoplastic lesions as induced by anthracyclines. In addition, we found that tumors treated with anthracyclines manifest increased expression levels of the chemokine Ccl2. Such a response is important as neoplasms growing in Ccl2(-/-) mice failed to accumulate dendritic cell-like APCs in response to chemotherapy. Moreover, cancers developing in mice lacking Ccl2 or its receptor (Ccr2) exhibited suboptimal therapeutic responses to anthracycline-based chemotherapy. Altogether, our results underscore the importance of the CCL2/CCR2 signaling axis for therapeutic anticancer immune responses as elicited by immunogenic chemotherapy. (C) 2013 AACR.
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.