The main research focus of the lab is the development, preclinical and clinical validation of T-cell based gene therapy approaches to treat cancer. We started the preclinical and clinical use of suicide gene therapy applied to allogeneic stem cell transplantation (allo-HSCT). This approach aims at benefitting from the graftversus-leukemia potential of allogeneic lymphocytes in the context of allo-HSCT, while selectively controlling graft-versus-host disease, their major complication. Pioneered in IRCCS Ospedale San Raffaele in the ‘90s (Bonini et al., Science 1997), optimized and tested in different academic and industry-sponsored clinical trials, the suicide gene therapy approach obtained approval from EMA in 2016, thus representing the first cell based gene therapy product approved for cancer patients in Europe. The many lessons learned with this first project have been more recently exploited in innovative projects designed to redirect T cell specificity against tumor antigens.
Recently we developed the TCR gene editing approach (Provasi, Genovese et al., Nat Med 2012; Mastaglio et al., Blood 2017). With this project we completely substitute T cell specificity by editing the genome of T cells with artificial nucleases and viral vectors, thus generating tumor-specific T lymphocytes.
The Immunomonitoring sub-Unit of the lab is dedicated to the identification of immunological correlates with clinical outcome in the context of allo-HSCT, cellular therapy and gene therapy.
Recently, we showed that central memory (TCM) and memory stem T cells (TSCM) are endowed with high expansion and persistence ability, and innovative protocols for their genetic engineering have been developed (reviewed in Gattinoni et al., Nat Med 2017).
The major aim of the lab today, is to actively participate to the exciting transition of cellular therapy from the investigational phase to the phase of real life by developing and validating innovative cellular therapy products.
Mastaglio S, Genovese P, Magnani Z, Ruggiero E, Landoni E, Camisa B, Schiroli G, Provasi E, Lombardo A, Reik A, Cieri N, Rocchi M, Oliveira G, Escobar G, Casucci M, Gentner B, Spinelli A, Mondino A, Bondanza A, Vago L, Ponzoni M, Ciceri F, Holmes M, Naldini L and Bonini C. NYESO- 1 TCR single edited central memory and memory stem T cells to treat multiple myeloma without inducing GvHD. Blood 2017 Aug 3;130(5):606-618.
Gattinoni L, Speiser DE, Lichterfeld, M, Bonini C. T memory stem cells in health and disease. Nat Med. 2017 Jan 6;23(1):18-27.
Oliveira G, Ruggiero E, Lupo Stanghellini MT, Cieri N, D’Agostino M, Fronza R, Lulay C, Dionisio F, Mastaglio S, Greco R, Peccator J, Aiuti A, Ambrosi A, Biasco L, Bondanza A, Lambiase A, Traversari C, Vago L, Von Kalle C, Schmidt M, Bordignon C, Ciceri F, Bonini C. Tracking genetically engineered lymphocytes long-term reveals the dynamics of T-cell immunological memory. Sci Transl Med. 2015 Dec 9;7(317):317ra198.
Cieri N, Oliveira G, Greco R, Forcato M, Taccioli C, Cianciotti B, Valtolina V, Noviello M, Vago L, Bondanza A, Lunghi F, Marktel S, Bellio L, Bordignon C, Bicciato S, Peccatori J, Ciceri F, and Bonini C. Generation of human memory stem T cells upon haploidentical T-replete hematopoietic stem cell transplantation. Blood 2015 Apr 30;125(18):2865-74.
Genovese P, Schiroli G, Escobar G, Di Tomaso T, Firrito C, Calabria A, Moi D, Mazzieri R, Bonini C, Holmes MC, Gregory PD, van der Burg M, Gentner B, Montini E, Lombardo A, Naldini L. Targeted Genome Editing in Human Repopulating Hematopoietic Stem Cells. Nature. 2014 Jun 2;510(7504):235-40
Casucci M, Perna SK, Falcone L, Camisa B, Magnani Z, Bernardi M, Crotta A, Tresoldi C, Fleischhauer K, Ponzoni M, Gregori S, Caligaris-Cappio F, Ciceri F, Bordignon C, Cignetti A, Bondanza A, Bonini C Graft-versus-leukemia effect of HLA-haploidentical central-memory T cells expanded with leukemic APCs and modified with a suicide gene. Mol Ther. 2013 Feb;21(2):466-75.
Provasi E, Genovese P, Lombardo A, Magnani Z, Liu PQ, Reik A, Chu V, Paschon DE, Zhang L, Kuball J, Camisa B, Bondanza A, Casorati G, Ponzoni M, Ciceri F, Bordignon C, Greenberg PD, Holmes MC, Gregory PD, Naldini L, Bonini C. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nature Medicine 2012 May;18(5):807-15.
Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Lupo-Stanghellini MT, Perrelli NF, Cosentino C, Torri F, Angius A, Forno B, Casucci M, Bernardi M, Peccatori J, Corti C, Bondanza A, Ferrari M, Rossini S, Roncarolo MG, Bordignon C, Bonini C, Ciceri F, Fleischhauer K. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009 Jul 30;361(5):478-88.
Ciceri F, Bonini C, (FC, CB, equal contribution), Lupo Stanghellini MT, Bondanza A, Traversari C, Salomoni M, Turchetto L, Colombi S, Bernardi M, Peccatori J, Pescarollo A, Servida P, Magnani Z, Perna SK, Valtolina V, Crippa F, Callegaro L, Spoldi E, Crocchiolo R, Fleischhauer K, Ponzoni M, Vago L, Rossini S, Santoro A, Todisco A, Apperley J, Olavarria E, Slavin S, Weissinger EM, Ganser A, Stadler M, Yannaki E, Fassas A, Anagnostopoulos A, Bregni M, Gallo Stampino C, Bruzzi P and Bordignon C. Infusion of suicide geneengineered donor lymphocytes after family haploidentical hemopoietic transplantation for leukemia: the TK007 phase I/II trial. Lancet Oncol. 2009 May;10(5):489-500.
Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, Mavilio F, Traversari C and Bordignon C. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versusleukemia. Science 1997; 276:1719-1724.
Pantaleo De Simone
Giulia Di Lullo
AIRC 5x1000 Program Manager