Vincenzo Russo

Publications (32)193.97 Total impact

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  Available from: Mario Santinami

  Article: Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes.

  Vincenzo Russo, Lorenzo Pilla, Francesca Lunghi, Roberto Crocchiolo, Raffaella Greco, Fabio Ciceri, Daniela Maggioni, Raffaella Fontana, Sylvain Mukenge, Licia Rivoltini, [......], Corrado Gallo-Stampino, Matteo Del Fiacco, Antonio Lambiase, Pierre G Coulie, Roberto Patuzzo, Giorgio Parmiani, Catia Traversari, Claudio Bordignon, Mario Santinami, Marco Bregni
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  ABSTRACT: Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3(+) melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90% and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with 1 objective clinical response, and 4 durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses. © 2012 Wiley Periodicals, Inc.
  International Journal of Cancer 11/2012; · 5.44 Impact Factor
• Article: Control of the immune system by oxysterols and cancer development.

  Catia Traversari, Vincenzo Russo
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  ABSTRACT: Oxysterols/oxysterol receptors have been shown to modulate several immune cell subsets, such as macrophages, T-cells and B-cells, neutrophils and dendritic cells (DCs). They participate in the control of several pathologic processes, that is, infectious diseases, atherosclerosis and autoimmunity. Moreover, some oxysterols have also been shown to favor tumor progression by dampening the antitumor immune response. The cellular responses generated by oxysterols depend on the engagement of Liver X Receptor (LXR) α and/or β isoforms, which induce activation of target genes or trans-repression of pro-inflammatory gene transcription. Recently, some reports have described a different mechanism of action of oxysterols, mediated by the engagement of G-Protein Coupled Receptors. Here, we summarize LXR-dependent and LXR-independent responses of oxysterols on immune cells with possible effects on tumor development.
  Current Opinion in Pharmacology 07/2012; · 6.86 Impact Factor
• Article: Ninth annual meeting of the Italian Network for Tumor Biotherapy (NIBIT), Siena, Italy, October 19-22, 2011: New perspectives in the immunotherapy of cancer.

  Michele Maio, Hugues J M Nicolay, Paolo A Ascierto, Filippo Belardelli, Roberto Camerini, Mario P Colombo, Paola Queirolo, Ruggero Ridolfi, Vincenzo Russo, Giulia Parisi, Ester Fonsatti, Michael Papamichail, Giorgio Parmiani
  Cancer Immunology and Immunotherapy 06/2012; 61(9):1599-608. · 3.70 Impact Factor
• Article: A dual role for genetically modified lymphocytes in cancer immunotherapy.

  Vincenzo Russo, Attilio Bondanza, Fabio Ciceri, Marco Bregni, Claudio Bordignon, Catia Traversari, Chiara Bonini
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  ABSTRACT: T cells as the ultimate effectors of adaptive immune responses are currently used to treat patients affected by infectious diseases and certain tumors. Recently, T cells have been manipulated ex vivo with viral vectors coding for chimeric antigen receptors, exogenous T cell receptors, or 'suicide' genes to potentiate their efficacy and minimize possible side effects. However, the introduction of exogenous genes into T lymphocytes, particularly bacterial or viral transgene products, has occasionally produced immune-mediated elimination of transduced lymphocytes. This immune effect has recently been exploited in a trial of active immunotherapy in melanoma patients. In this opinion article, we discuss the therapeutic possibilities presented by the dual aspects of genetically modified lymphocytes used to treat cancer patients.
  Trends in Molecular Medicine 01/2012; 18(4):193-200. · 10.35 Impact Factor
• Article: Autologous versus allogeneic cell-based vaccines?

  Giorgio Parmiani, Lorenzo Pilla, Cristina Maccalli, Vincenzo Russo
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  ABSTRACT: Devitalized tumor cells either autologous or allogeneic have been used as anti-cancer vaccines with the purpose of facilitating the induction of an immune response able to destroy growing tumor cells since the identification of tumor antigens was deemed not to be necessary, particularly in the autologous system. Such vaccines were tested first in animal models and then in the clinics as unmodified tumor cells or after insertion of genes coding for factors known to increase the immune response against tumors. These vaccines were usually given by subcutaneous injections along with different immunological adjuvants. Such immunization approaches were found to be effective in mice when carried out in a tumor preventive setting but significantly less in the therapeutic context, that is, in the presence of an established tumor. By analyzing several clinical trials of vaccination using either autologous or allogeneic unmodified and gene-modified tumor cells published in the last 10 to 15 years, we conclude for a lack of sufficient evidence for efficacy of this strategy in inducing both a strong immune response and a therapeutic response. A potential variant of this strategy is the direct intratumoral injection of immunostimulatory genes delivered by vectors in vivo. But even this approach failed to provide a statistically significant clinical benefit for the cancer patients.We also point out the inherent drawbacks of the tumor cell-based vaccine strategy that include (a) a limited frequency by which human tumor lines can be obtained from clinical samples, (b) the low number of available cells for vaccination, (c) the release of immune-suppressive factors by tumor cells, and (d) the cost and time necessary for standardization and collecting/expanding a number of cells according to the approved regulatory requirements. Thus, taking into consideration the new developments in cancer vaccines, we believe that tumor cell-based vaccines should be dismissed as anti-cancer vaccines unless a clear benefit could be demonstrated by the few ongoing trials of combination with new immunomodulating reagents (eg, anti-CTLA4, PD-1, chemotherapy).
  The Cancer Journal 09/2011; 17(5):331-6. · 3.26 Impact Factor
• Article: Eighth annual meeting of the Italian network for tumor biotherapy (NIBIT), Siena, October 7-9, 2010.

  Michele Maio, Hugues J M Nicolay, Paolo A Ascierto, Filippo Belardelli, Roberto Camerini, Mario P Colombo, Paola Queirolo, Ruggero Ridolfi, Vincenzo Russo, Ester Fonsatti, Giorgio Parmiani
  Cancer Immunology and Immunotherapy 03/2011; 60(6):901-7. · 3.70 Impact Factor
• Source

  Available from: PubMed Central

  Article: A Clinical Study of a Cell-Based MAGE-A3 Active Immunotherapy in Advanced Melanoma Patients.

  Vincenzo Russo, Francesca Lunghi, Raffaella Fontana, Marco Bregni
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  ABSTRACT: In this bi-institutional study, twenty-three stage IIIC-IV MAGE-A3(+) melanoma patients were vaccinated with M3TK-GML biweekly at three dose levels, with a subsequent phase of vaccinations at the maximum dose level. Anti-MAGE-A3 and anti-TK T cells were assessed by in vitro assay and delayed-type hypersensitivity skin testing.
  Journal of Cancer. 01/2011; 2:329-30.
• Article: Seventh annual meeting of the Italian Network for Tumor Biotherapy (NIBIT), Siena, 1-3 October 2009.

  Michele Maio, Hugues J M Nicolay, Paolo A Ascierto, Filippo Belardelli, Roberto Camerini, Mario P Colombo, Paola Queirolo, Ruggero Ridolfi, Vincenzo Russo, Ester Fonsatti, Giorgio Parmiani
  Cancer Immunology and Immunotherapy 03/2010; 59(12):1895-901. · 3.70 Impact Factor
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  Available from: Martine Behra

  Article: Molecular dissection of the migrating posterior lateral line primordium during early development in zebrafish.

  Viviana E Gallardo, Jin Liang, Martine Behra, Abdel Elkahloun, Eduardo J Villablanca, Vincenzo Russo, Miguel L Allende, Shawn M Burgess
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  ABSTRACT: Development of the posterior lateral line (PLL) system in zebrafish involves cell migration, proliferation and differentiation of mechanosensory cells. The PLL forms when cranial placodal cells delaminate and become a coherent, migratory primordium that traverses the length of the fish to form this sensory system. As it migrates, the primordium deposits groups of cells called neuromasts, the specialized organs that contain the mechanosensory hair cells. Therefore the primordium provides both a model for studying collective directional cell migration and the differentiation of sensory cells from multipotent progenitor cells. Through the combined use of transgenic fish, Fluorescence Activated Cell Sorting and microarray analysis we identified a repertoire of key genes expressed in the migrating primordium and in differentiated neuromasts. We validated the specific expression in the primordium of a subset of the identified sequences by quantitative RT-PCR, and by in situ hybridization. We also show that interfering with the function of two genes, f11r and cd9b, defects in primordium migration are induced. Finally, pathway construction revealed functional relationships among the genes enriched in the migrating cell population. Our results demonstrate that this is a robust approach to globally analyze tissue-specific expression and we predict that many of the genes identified in this study will show critical functions in developmental events involving collective cell migration and possibly in pathological situations such as tumor metastasis.
  BMC Developmental Biology 01/2010; 10:120. · 2.79 Impact Factor
• Article: Molecular dissection of the migrating posterior lateral line primordium during early development in zebrafish

  Viviana Gallardo, Jin Liang, Martine Behra, Abdel Elkahloun, Eduardo Villablanca, Vincenzo Russo, Miguel Allende, Shawn Burgess
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  ABSTRACT: Abstract Background Development of the posterior lateral line (PLL) system in zebrafish involves cell migration, proliferation and differentiation of mechanosensory cells. The PLL forms when cranial placodal cells delaminate and become a coherent, migratory primordium that traverses the length of the fish to form this sensory system. As it migrates, the primordium deposits groups of cells called neuromasts, the specialized organs that contain the mechanosensory hair cells. Therefore the primordium provides both a model for studying collective directional cell migration and the differentiation of sensory cells from multipotent progenitor cells. Results Through the combined use of transgenic fish, Fluorescence Activated Cell Sorting and microarray analysis we identified a repertoire of key genes expressed in the migrating primordium and in differentiated neuromasts. We validated the specific expression in the primordium of a subset of the identified sequences by quantitative RT-PCR, and by in situ hybridization. We also show that interfering with the function of two genes, f11r and cd9b, defects in primordium migration are induced. Finally, pathway construction revealed functional relationships among the genes enriched in the migrating cell population. Conclusions Our results demonstrate that this is a robust approach to globally analyze tissue-specific expression and we predict that many of the genes identified in this study will show critical functions in developmental events involving collective cell migration and possibly in pathological situations such as tumor metastasis.
  BMC Developmental Biology. 01/2010;
• Source

  Available from: Aurora Negro

  Article: Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses.

  Eduardo J Villablanca, Laura Raccosta, Dan Zhou, Raffaella Fontana, Daniela Maggioni, Aurora Negro, Francesca Sanvito, Maurilio Ponzoni, Barbara Valentinis, Marco Bregni, Alessandro Prinetti, Knut R Steffensen, Sandro Sonnino, Jan-Ake Gustafsson, Claudio Doglioni, Claudio Bordignon, Catia Traversari, Vincenzo Russo
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  ABSTRACT: Sterol metabolism has recently been linked to innate and adaptive immune responses through liver X receptor (LXR) signaling. Whether products of sterol metabolism interfere with antitumor responses is currently unknown. Dendritic cells (DCs) initiate immune responses, including antitumor activity after their CC chemokine receptor-7 (CCR7)-dependent migration to lymphoid organs. Here we report that human and mouse tumors produce LXR ligands that inhibit CCR7 expression on maturing DCs and, therefore, their migration to lymphoid organs. In agreement with this observation, we detected CD83(+)CCR7(-) DCs within human tumors. Mice injected with tumors expressing the LXR ligand-inactivating enzyme sulfotransferase 2B1b (SULT2B1b) successfully controlled tumor growth by regaining DC migration to tumor-draining lymph nodes and by developing overt inflammation within tumors. The control of tumor growth was also observed in chimeric mice transplanted with bone marrow from mice lacking the gene encoding LXR-alpha (Nr1h3(-/-) mice) Thus, we show a new mechanism of tumor immunoescape involving products of cholesterol metabolism. The manipulation of this pathway could restore antitumor immunity in individuals with cancer.
  Nature medicine 01/2010; 16(1):98-105. · 27.14 Impact Factor
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  Available from: hematologylibrary.org

  Article: The hidden (and lazy) TCR.

  Chiara Bonini, Vincenzo Russo
  Blood 10/2009; 114(14):2855-6. · 9.90 Impact Factor
• Article: Sixth annual meeting of the Italian network for tumor biotherapy (NIBIT), Siena, 16-18 October 2008.

  Michele Maio, Hugues J M Nicolay, Paolo A Ascierto, Filippo Belardelli, Roberto Camerini, Mario P Colombo, Paola Queirolo, Ruggero Ridolfi, Vincenzo Russo, Ester Fonsatti, Giorgio Parmiani
  Cancer Immunology and Immunotherapy 04/2009; 59(6):963-9. · 3.70 Impact Factor
• Article: Peripheral blood lymphocytes genetically modified to express the self/tumor antigen MAGE-A3 induce antitumor immune responses in cancer patients.

  Raffaella Fontana, Marco Bregni, Arcadi Cipponi, Laura Raccosta, Cristina Rainelli, Daniela Maggioni, Francesca Lunghi, Fabio Ciceri, Sylvain Mukenge, Claudio Doglioni, Didier Colau, Pierre G Coulie, Claudio Bordignon, Catia Traversari, Vincenzo Russo
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  ABSTRACT: Dendritic cell (DC) targeting in vivo has recently been shown to confer strong and protective cytotoxic T lymphocyte (CTL)-based immunity in tumor murine models. Our group has recently demonstrated in preclinical models that the infusion of genetically modified lymphocytes (GMLs) expressing the self/tumor antigen TRP-2 is able to elicit functional TRP-2-specific effectors with antitumor activity by targeting DCs in vivo. Here we have analyzed vaccine- and tumor-specific immune responses of 10 melanoma patients treated with autologous GMLs expressing the cancer germline gene MAGE-A3. Three of 10 patients treated with MAGE-A3-GML showed an increase of circulating anti-MAGE-A3 T cells, and developed skin delayed-type hypersensitivity to MAGE-A3. Interestingly, in 2 of these patients, with progressive and measurable tumors at study entry, anti-MAGE-A3 T cells were detected not only in the blood but also within tumors resected after vaccination. These results demonstrate that the infusion of MAGE-A3-GML elicits antitumor T cells, which are capable of trafficking to inflamed tissues and of infiltrating tumors. Clinical studies on a larger group of patients are needed to evaluate the clinical efficacy of such a strategy.
  Blood 01/2009; 113(8):1651-60. · 9.90 Impact Factor
• Article: IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes.

  Shin Kaneko, Sara Mastaglio, Attilio Bondanza, Maurilio Ponzoni, Francesca Sanvito, Luca Aldrighetti, Marina Radrizzani, Simona La Seta-Catamancio, Elena Provasi, Anna Mondino, Toshiro Nagasawa, Katharina Fleischhauer, Vincenzo Russo, Catia Traversari, Fabio Ciceri, Claudio Bordignon, Chiara Bonini
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  ABSTRACT: Long-term clinical remissions of leukemia, after allogeneic hematopoietic stem cell transplantation, depend on alloreactive memory T cells able to self-renew and differentiate into antileukemia effectors. This is counterbalanced by detrimental graft-versus-host disease (GVHD). Induction of a selective suicide in donor T cells is a current gene therapy approach to abrogate GVHD. Unfortunately, genetic modification reduces alloreactivity of lymphocytes. This associates with an effector memory (T(EM)) phenotype of gene-modified lymphocytes and may limit antileukemia effect. We hypothesized that alloreactivity of gene-modified lymphocytes segregates with the central memory (T(CM)) phenotype. To this, we generated suicide gene-modified T(CM) lymphocytes with a retroviral vector after CD28 costimulation and culture with IL-2, IL-7, or a combination of IL-7 and IL-15. In vitro, suicide gene-modified T(CM) cells self-renewed upon alloantigen stimulation and resisted activation-induced cell death. In a humanized mouse model, only suicide gene-modified T cells cultured with IL-7 and IL-15 persisted, differentiated in T(EM) cells, and were as potent as unmanipulated lymphocytes in causing GVHD. GVHD was halted through the activation of the suicide gene machinery. These results warrant the use of suicide gene-modified T(CM) cells cultured with IL-7 and IL-15 for the safe exploitation of the alloreactive response against cancer.
  Blood 11/2008; 113(5):1006-15. · 9.90 Impact Factor
• Article: Dendritic cell migration and lymphocyte homing imprinting.

  Eduardo J Villablanca, Vincenzo Russo, J Rodrigo Mora
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  ABSTRACT: For an effective adaptive immune response to occur, dendritic cells (DC), which are the most efficient antigen-presenting cells, must be able to sample the peripheral microenvironment and migrate towards secondary lymphoid organs (SLO) where they activate naive lymphocytes. Upon activation, lymphocytes proliferate and acquire the capacity to migrate to extralymphoid compartments. Although the molecular mechanisms controlling lymphocyte homing to lymphoid and to some extralymphoid tissues have been described in significant detail, it is much less clear how DC migration is controlled. Do DC obey similar adhesion cues that lymphocytes do, or do they have their own "zip codes"? This is relevant from a therapeutic standpoint because effective DC-based vaccines should be able to reach the appropriate tissues in order to generate protective immune responses. Here, we discuss some of the mechanisms used by DC to reach their target tissues. Once DC arrive at their destination, they are exposed to the tissue microenvironment, which likely modulates their functional properties in a tissue-specific fashion. This local DC "education" is probably responsible among other things; for the acquisition of tissue-specific homing imprinting capacity by which DC instruct lymphocytes to migrate to specific tissues. Finally, we discuss how dysregulation of these signals may play a key role in disease.
  Histology and histopathology 08/2008; 23(7):897-910. · 2.48 Impact Factor
• Article: Selected natural and synthetic retinoids impair CCR7- and CXCR4-dependent cell migration in vitro and in vivo.

  Eduardo J Villablanca, Dan Zhou, Barbara Valentinis, Aurora Negro, Laura Raccosta, Laura Mauri, Alessandro Prinetti, Sandro Sonnino, Claudio Bordignon, Catia Traversari, Vincenzo Russo
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  ABSTRACT: Dendritic cell (DC) migration to secondary lymphoid organs is a crucial step to initiate adaptive immune responses. This step requires the expression of a functional CCR7 chemokine receptor on DC undergoing maturation. Here, we show that the natural retinoid 9-cis retinoic acid (9cRA) and the synthetic retinoid fenretinide (4-HPR) specifically inhibit the functional up-regulation of CCR7 on maturing human DCs, without affecting early steps of DC maturation. As a consequence, mature DCs do not migrate in vitro toward the chemokine CCL19. Importantly, 4-HPR and 9cRA by inhibiting the expression of CCR7 on bone marrow-derived murine DCs dampen their in vivo migration to draining lymph nodes. 4-HPR also inhibits the expression of the chemokine receptors CXCR4, therefore, impairing in vitro migration of human DCs to CXCL12 and inhibiting in vivo the CXCR4-dependent migration of the posterior lateral line primordium (PLLp) in zebrafish embryos. Taken together, these data highlight a novel function of retinoids and suggest the possibility of using retinoids to treat inflammatory or autoimmune diseases.
  Journal of Leukocyte Biology 06/2008; 84(3):871-9. · 4.99 Impact Factor
• Article: Endosomal proteases influence the repertoire of MAGE-A3 epitopes recognized in vivo by CD4+ T cells.

  Jill Marturano, Renato Longhi, Vincenzo Russo, Maria Pia Protti
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  ABSTRACT: Little is known about the repertoire of MAGE-A3 CD4(+) T-cell epitopes recognized in vivo by neoplastic patients and how antigen processing influences epitope formation. Here, we first show that MAGE-A3-specific CD4(+) T cells are present in the blood of advanced melanoma patients. MAGE-A3(111-125), MAGE-A3(191-205), and MAGE-A3(281-300) were recognized by 7, 6, and 5 of the 11 patients tested, respectively. MAGE-A3(146-160) and MAGE-A3(171-185) were also recognized in two and one cases, whereas no recognition of MAGE-A3(161-175) and MAGE-A3(243-258) was observed. Cytokines produced were mainly interleukin 5 and/or granulocyte macrophage colony-stimulating factor, suggesting impairment of productive polarized Th1 responses. Secondly, proteases inhibitors were used to modulate in vitro the recognition by CD4(+) T-cells clones of dendritic cells loaded with MAGE-A3-expressing cell lysates. We found that formation of MAGE-A3(111-125) depended on both leupeptin-sensitive and pepstatin-sensitive proteases. In contrast, we found that MAGE-A3(161-175), which was never recognized ex vivo, was formed by leupeptin but destroyed by pepstatin-sensitive proteases. Collectively, our results show that (a) anti-MAGE-A3 CD4(+) T-cell immunity develops in vivo in neoplastic patients and is focused toward immunodominant epitopes, (b) the response in advanced disease is skewed toward a Th2 type, and (c) endosomal/lysosomal proteases in dendritic cells influence the repertoire of the epitopes recognized.
  Cancer Research 04/2008; 68(5):1555-62. · 7.86 Impact Factor
• Article: Update on vaccines for melanoma patients

  Vincenzo Russo, Cristina Maccalli, Lorenzo Pilla, Santo Raffaele Mercuri, Elena Orsenigo, Sylvain Mukenge, Marco Bregni, Giorgio Parmiani
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  ABSTRACT: Vaccination against melanoma has a long history but only recently has this therapeutic approach found a reliable scientific rationale. This review summarizes and updates the knowledge on the role of the main players in the vaccination strategy against metastatic melanoma, that is, the melanoma-associated antigens recognized by T and natural killer T lymphocytes, the conditions for the immune response to develop and the mechanisms that interfere with it. A commented list of the major vaccination trials whose results have been recently published or are ongoing is also presented. Reasons for failure and potential success are underlined to offer a balanced view of this scientifically exciting but still clinically unrewarding field of investigation.
  Expert Review of Dermatology 03/2008; 3(2):195-207.
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  Available from: PubMed Central

  Article: The Italian Network for Tumor Biotherapy (NIBIT): getting together to push the field forward.

  Michele Maio, Hugues Jm Nicolay, Paolo Ascierto, Filippo Belardelli, Roberto Camerini, Mario P Colombo, Paola Queirolo, Ruggero Ridolfi, Vincenzo Russo, Lucia Anzalone, Ester Fonsatti, Giorgio Parmiani
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  ABSTRACT: As for a consolidated tradition, the 5th annual meeting of the Italian Network for Cancer Biotherapy took place in the Certosa of Pontignano, a Tuscan monastery, on September 20-22, 2007. The congress gathered more than 40 Italian leading groups representing academia, biotechnology and pharmaceutical industry. Aim of the meeting was to share new advances in cancer bio-immunotherapy and to promote their swift translation from pre-clinical research to clinical applications. Several topics were covered including: a) molecular and cellular mechanisms of tumor escape; b) therapeutic antibodies and recombinant constructs; c) clinical trials up-date and new programs; d) National Cooperative Networks and their potential interactions; e) old and new times in cancer immunology, an "amarcord". Here, we report the main issues discussed during the meeting.
  Journal of Translational Medicine 02/2008; 6:8. · 3.41 Impact Factor