Mario Luppi
e-mail: mario.luppi AT unimore.it
affiliation: Università di Modena-Reggio Emilia
research area(s): Immunity And Infection, Experimental Medicine
Course:
Molecular and Regenerative Medicine
University/Istitution: Università di Modena-Reggio Emilia
University/Istitution: Università di Modena-Reggio Emilia
Mario Luppi is Full Professor of Hematology. He is internationally recognized expert in epidemiological and biological studies of the association between human viruses and neoplastic and non-neoplastic hematological diseases and Kaposi sarcoma. He has published 150 scientific articles in prestigious journals as well as reviews and book chapters in the field of Haematology. He has received major project grants from the Italian Ministry of University and Scientific and Technological Research, from the Italian Ministry of Defence, from European Community (FP6), from industries and private Associations. His work has been awarded with different prizes.
• At present, Chief of Division of Hematology at the Department of Oncology, Hematology and Respiratory Diseases, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria, Policlinico, Via del Pozzo, 71 - 41124 Modena, IT
• Vice-President of the Italian Society of Experimental Haematology (SIES) from 2007 to 2008
• Associate Professor in Haematology, in 2003
• General Secretary of the Italian Society of Experimental Haematology (SIES) from 2002 to 2006
• University Researcher in Haematology, in 1999
• PhD course in Experimental Haematology from 1994 to 1997;
• Specialty in Clinical Haematology at the University of Modena, in 1993;
• Fellow at the Institute “Mario Negri”, Milano, IT, at the Unit of Differentiation and Molecular Biology, directed by Dr. M. Introna, in the Laboratory of Immunology, directed by Dr. A. Mantovani, from 1993 to 1994;
• Residency in Haematology and Internal Medicine Branches of the University of Modena, from 1990 to 1993;
• Research Fellow at the Department of Immunology directed by Dr. Fox, at the Scripps clinic, La Jolla, CA, USA, in 1990;
• Graduation in Medicine & Surgery with 110/110 cum Laude at the University of Modena, in 1989.
• At present, Chief of Division of Hematology at the Department of Oncology, Hematology and Respiratory Diseases, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria, Policlinico, Via del Pozzo, 71 - 41124 Modena, IT
• Vice-President of the Italian Society of Experimental Haematology (SIES) from 2007 to 2008
• Associate Professor in Haematology, in 2003
• General Secretary of the Italian Society of Experimental Haematology (SIES) from 2002 to 2006
• University Researcher in Haematology, in 1999
• PhD course in Experimental Haematology from 1994 to 1997;
• Specialty in Clinical Haematology at the University of Modena, in 1993;
• Fellow at the Institute “Mario Negri”, Milano, IT, at the Unit of Differentiation and Molecular Biology, directed by Dr. M. Introna, in the Laboratory of Immunology, directed by Dr. A. Mantovani, from 1993 to 1994;
• Residency in Haematology and Internal Medicine Branches of the University of Modena, from 1990 to 1993;
• Research Fellow at the Department of Immunology directed by Dr. Fox, at the Scripps clinic, La Jolla, CA, USA, in 1990;
• Graduation in Medicine & Surgery with 110/110 cum Laude at the University of Modena, in 1989.
• biology and pathogenetic role of lymphotropic viruses in neoplastic and non-neoplastic hematologic diseases;
• molecular pathogenesis and new therapeutic approaches for leukemias and lymphomas;
• molecular and inflammatory pathogenesis and new therapeutic approaches (T-cell therapy) for Kaposi's sarcoma;
• pathogenesis and diagnosis of post-transplant (solid organ and bone marrow) neoplasias and infectious diseases;
• implementation of diagnostic activities for hematologic neoplasias, research and validation of new molecular and immunological biomarkers for leukemias;
• pathogenesis and immunological diagnosis for invasive fungal infections
GRANTS (last 5 Yrs):
1. 2005/10 “The role of chronic infections in the development of cancer” (FP6-EU)
2. 2005/07 “Analysis of genetic-immunologic factors and identification of new biomarkers in post-transplant Kaposi sarcoma” (AIRC)
3. 2007-2009 “Immunità nel trapiantato di organo solido/midollo osseo/staminali periferiche: validazione ed applicazione di nuovi tests in una gestione regionale coordinata della diagnosi e monitoraggio delle complicanze infettive post-trapianto” (Regione Emilia Romagna, PRU)
4. 2008-2010 “Multicenter Study on the Enumeration of Aspergillus-specific T cells through an Ex-vivo Enzyme Linked Immunospot Assay for the Diagnosis of Invasive Aspergillosis in Hematologic Patients” (Merck Sharp & Dohme)
5. 2008-2010 “Studio dei polimorfismi nei geni di riconoscimento di strutture molecolari di patogeni (TLRs) nei pazienti ematologici: correlazione con lo sviluppo e l’andamento clinico dell’aspergillosi invasiva” (Schering)
6. 2010 “Exploiting HHV8-specific T-cell immunity to optimize treatment of Kaposi sarcoma” (AIRC)
7. 2010-2012 Studio multicentrico “Identification of specific T cells to demonstrate the exposure to fungi of the order Mucorales in patients at high risk for invasive mold infections” (Gilead)
• molecular pathogenesis and new therapeutic approaches for leukemias and lymphomas;
• molecular and inflammatory pathogenesis and new therapeutic approaches (T-cell therapy) for Kaposi's sarcoma;
• pathogenesis and diagnosis of post-transplant (solid organ and bone marrow) neoplasias and infectious diseases;
• implementation of diagnostic activities for hematologic neoplasias, research and validation of new molecular and immunological biomarkers for leukemias;
• pathogenesis and immunological diagnosis for invasive fungal infections
GRANTS (last 5 Yrs):
1. 2005/10 “The role of chronic infections in the development of cancer” (FP6-EU)
2. 2005/07 “Analysis of genetic-immunologic factors and identification of new biomarkers in post-transplant Kaposi sarcoma” (AIRC)
3. 2007-2009 “Immunità nel trapiantato di organo solido/midollo osseo/staminali periferiche: validazione ed applicazione di nuovi tests in una gestione regionale coordinata della diagnosi e monitoraggio delle complicanze infettive post-trapianto” (Regione Emilia Romagna, PRU)
4. 2008-2010 “Multicenter Study on the Enumeration of Aspergillus-specific T cells through an Ex-vivo Enzyme Linked Immunospot Assay for the Diagnosis of Invasive Aspergillosis in Hematologic Patients” (Merck Sharp & Dohme)
5. 2008-2010 “Studio dei polimorfismi nei geni di riconoscimento di strutture molecolari di patogeni (TLRs) nei pazienti ematologici: correlazione con lo sviluppo e l’andamento clinico dell’aspergillosi invasiva” (Schering)
6. 2010 “Exploiting HHV8-specific T-cell immunity to optimize treatment of Kaposi sarcoma” (AIRC)
7. 2010-2012 Studio multicentrico “Identification of specific T cells to demonstrate the exposure to fungi of the order Mucorales in patients at high risk for invasive mold infections” (Gilead)
1. Potenza L, Barozzi P, Torelli G, Luppi M. (2010) Translational challenges of human herpesvirus 6 chromosomal integration. Future Microbiol;5(7):993-5.
2. Riva G, Luppi M, Barozzi P, Quadrelli C, Basso S, Vallerini D, Zanetti E, Morselli M, Forghieri F, Maccaferri M, Volzone F, Del Giovane C, D'Amico R, Locatelli F, Torelli G, Comoli P, Potenza L. (2010) Emergence of BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during long-term imatinib mesylate treatment. Blood;115(8):1512-8
3. Potenza L, Barozzi P, Masetti M, Pecorari M, Bresciani P, Gautheret-Dejean A, Riva G, Vallerini D, Tagliazucchi S, Codeluppi M, Di Benedetto F, Gerunda GE, Narni F, Torelli G, Luppi M. (2009) Prevalence of human herpesvirus-6 chromosomal integration (CIHHV-6) in Italian solid organ and allogeneic stem cell transplant patients. Am J Transplant. 2009;9(7):1690-7.
4. Barozzi P, Bonini C, Potenza L, Masetti M, Cappelli G, Gruarin P, Whitby D, Gerunda GE, Mondino A, Riva G, Vallerini D, Quadrelli C, Bosco R, Ciceri F, Bordignon C, Schulz TF, Torelli G, Luppi M. (2008) Changes in the immune responses against human herpesvirus-8 in the disease course of posttransplant Kaposi sarcoma. Transplantation;86(5):738-44.
5. Potenza L, Luppi M, Barozzi P, Rossi G, Cocchi S, Codeluppi M, Pecorari M, Masetti M, Di Benedetto F, Gennari W, Portolani M, Gerunda GE, Lazzarotto T, Landini MP, Schulz TF, Torelli G, Guaraldi G. (2008) HHV-6A in syncytial giant-cell hepatitis. N Engl J Med;359(6):593-602.
2. Riva G, Luppi M, Barozzi P, Quadrelli C, Basso S, Vallerini D, Zanetti E, Morselli M, Forghieri F, Maccaferri M, Volzone F, Del Giovane C, D'Amico R, Locatelli F, Torelli G, Comoli P, Potenza L. (2010) Emergence of BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during long-term imatinib mesylate treatment. Blood;115(8):1512-8
3. Potenza L, Barozzi P, Masetti M, Pecorari M, Bresciani P, Gautheret-Dejean A, Riva G, Vallerini D, Tagliazucchi S, Codeluppi M, Di Benedetto F, Gerunda GE, Narni F, Torelli G, Luppi M. (2009) Prevalence of human herpesvirus-6 chromosomal integration (CIHHV-6) in Italian solid organ and allogeneic stem cell transplant patients. Am J Transplant. 2009;9(7):1690-7.
4. Barozzi P, Bonini C, Potenza L, Masetti M, Cappelli G, Gruarin P, Whitby D, Gerunda GE, Mondino A, Riva G, Vallerini D, Quadrelli C, Bosco R, Ciceri F, Bordignon C, Schulz TF, Torelli G, Luppi M. (2008) Changes in the immune responses against human herpesvirus-8 in the disease course of posttransplant Kaposi sarcoma. Transplantation;86(5):738-44.
5. Potenza L, Luppi M, Barozzi P, Rossi G, Cocchi S, Codeluppi M, Pecorari M, Masetti M, Di Benedetto F, Gennari W, Portolani M, Gerunda GE, Lazzarotto T, Landini MP, Schulz TF, Torelli G, Guaraldi G. (2008) HHV-6A in syncytial giant-cell hepatitis. N Engl J Med;359(6):593-602.
Project Title:
Exploiting HHV8-specific T-cell immunity to optimize treatment of Kaposi sarcoma (AIRC2010)
BACKGROUND AND RATIONALE. Kaposi Sarcoma (KS) is a Human-Herpesvirus-8 (HHV8)-driven bulky tumor, diffusely affecting skin and viscera of solid organ recipients (post-transplant-KS) as well as Mediterranean elderly men (classic-KS). KS is usually treated with reduction/switch of immunosuppressive regimens and/or aggressive chemotherapy(CHT)-based therapies, but high rates of allograft rejection and severe systemic toxicities frequently impair the feasibility of these therapeutic approaches.
During the last 15 years, the wide knowledge on Epstein-Barr virus (EBV)-specific immunity has fostered effective development and successful clinical trials of adoptive T-cell therapies for patients with EBV-related neoplasms (PTLDs, HL, NPC). Conversely, similar immunological data on HHV8-specific T-cell subsets are lacking, while the direct antineoplastic activity of anti-HHV8 cytotoxic-T-cells (CTL) and the development of immunotherapeutic CTL-based protocols for KS patients have never so far been investigated.
AIMS AND DESCRIPTION OF THE PROJECT. To address these biological and clinical issues, the broad functional analysis of HHV8-antigen-specific T-cell responses and the feasibility of selection of “best-fit” anti-HHV8 CTL lines, as valuable immunological prognostic tool and effective therapy for KS patients, will be explored by pursuing the following strategies:
i) A first section will be focused on fine characterization of HHV8-specific T-cell subsets during immunological follow-up in KS+/KS- patients. We will longitudinally collect several time-point samples of peripheral-blood-mononuclear-cells (PBMCs), bone-marrow-mononuclear-cells (BMMCs) and skin-KS biopsies from renal/liver transplant KS patients on different immunosuppressive therapies, from classic KS patients undergoing diverse therapeutic approaches (systemic-CHT, electro-CHT, or “out-of-therapy” observation), as well as control samples from either HHV8+ organ recipients or HHV8+ aged individuals, without evidence of KS. On these samples, we will perform an array of functional antigen-specific immunoassays (EliSpot, Cytokine Secretion Assay, intracellular-cytokine flow cytometry) to describe the immune dynamics of pivotal CD8+/CD4+ T-cell subsets (CD8+CTL/Th1/Th2/Treg/Th17), specifically directed toward panels of HHV8-derived lytic/latent antigens (used as full-length recombinant proteins or spanned into short/long peptides). This will provide novel useful information for the biological comprehension of KS immune pathogenesis and for the prognostic optimization of immunological monitoring tools in patients at risk of/with KS.
ii) A second section will be dedicated to developing and testing several strategies to obtain ex-vivo preferential activation and in-vitro expansion of highly-cytotoxic HHV8-specific CTL lines, raised against the best available immunodominant target antigens, with clinical perspectives for the immunotherapeutic control of KS. Starting from the most suitable patients’ samples, as identified by the previous task, we intend to generate HHV8-specific CTLs by applying a wide panel of stimulation strategies (in the first instance, employment of different HHV8 lytic/latent antigens, full-length/spanned into short/long peptides, to pulse autologous monocytes or dendritic cells), and then test CTL-associated cytotoxic activity on different types of HHV8+ target cells, after short/long-term coltures. In case of promising pre-clinical results, we will evaluate efficacy and safety of HHV8-specific CTL infusions to treat “out-of-therapy” classic-KS patients.
During the last 15 years, the wide knowledge on Epstein-Barr virus (EBV)-specific immunity has fostered effective development and successful clinical trials of adoptive T-cell therapies for patients with EBV-related neoplasms (PTLDs, HL, NPC). Conversely, similar immunological data on HHV8-specific T-cell subsets are lacking, while the direct antineoplastic activity of anti-HHV8 cytotoxic-T-cells (CTL) and the development of immunotherapeutic CTL-based protocols for KS patients have never so far been investigated.
AIMS AND DESCRIPTION OF THE PROJECT. To address these biological and clinical issues, the broad functional analysis of HHV8-antigen-specific T-cell responses and the feasibility of selection of “best-fit” anti-HHV8 CTL lines, as valuable immunological prognostic tool and effective therapy for KS patients, will be explored by pursuing the following strategies:
i) A first section will be focused on fine characterization of HHV8-specific T-cell subsets during immunological follow-up in KS+/KS- patients. We will longitudinally collect several time-point samples of peripheral-blood-mononuclear-cells (PBMCs), bone-marrow-mononuclear-cells (BMMCs) and skin-KS biopsies from renal/liver transplant KS patients on different immunosuppressive therapies, from classic KS patients undergoing diverse therapeutic approaches (systemic-CHT, electro-CHT, or “out-of-therapy” observation), as well as control samples from either HHV8+ organ recipients or HHV8+ aged individuals, without evidence of KS. On these samples, we will perform an array of functional antigen-specific immunoassays (EliSpot, Cytokine Secretion Assay, intracellular-cytokine flow cytometry) to describe the immune dynamics of pivotal CD8+/CD4+ T-cell subsets (CD8+CTL/Th1/Th2/Treg/Th17), specifically directed toward panels of HHV8-derived lytic/latent antigens (used as full-length recombinant proteins or spanned into short/long peptides). This will provide novel useful information for the biological comprehension of KS immune pathogenesis and for the prognostic optimization of immunological monitoring tools in patients at risk of/with KS.
ii) A second section will be dedicated to developing and testing several strategies to obtain ex-vivo preferential activation and in-vitro expansion of highly-cytotoxic HHV8-specific CTL lines, raised against the best available immunodominant target antigens, with clinical perspectives for the immunotherapeutic control of KS. Starting from the most suitable patients’ samples, as identified by the previous task, we intend to generate HHV8-specific CTLs by applying a wide panel of stimulation strategies (in the first instance, employment of different HHV8 lytic/latent antigens, full-length/spanned into short/long peptides, to pulse autologous monocytes or dendritic cells), and then test CTL-associated cytotoxic activity on different types of HHV8+ target cells, after short/long-term coltures. In case of promising pre-clinical results, we will evaluate efficacy and safety of HHV8-specific CTL infusions to treat “out-of-therapy” classic-KS patients.