Chiara Bonini

Experimental hematology

Chiara Bonini, Head of Unit

Gene Therapy and Immunotherapy of Hematologic Malignancies. Hematologic malignancies, such as leukemia and lymphoma are among the most frequent human cancers. Pre-clinical and clinical studies, including bone marrow transplantation studies, demonstrated that the immune system plays a crucial role in controlling these diseases. The main goals of the laboratory are to investigate, potentiate and exploit the mechanisms underlying the immune response to hematologic malignancies through the genetic manipulation of lymphocytes.

Research activities (updated 2013)

Cancer immunotherapy with genetically engineered T lymphocytes

Cancer immunotherapy aims at harnessing the power and specificity of the immune system, well documented by its ability to combat infectious pathogens, to treat cancer. This approach has been limited, for several years, by a combination of biological and technological factors, including immune escape mechanisms adopted by tumors, the lower immunogenicity of cancer cells compared to infectious pathogens and pre-existing tolerance toward tumor-associated (TAA), but often not tumor-specific, antigens. We exploit gene transfer techniques to overcome these limitations and to generate long lasting tumor-reactive T lymphocytes to treat patients affected by hematological malignancies (Cieri, Immunol. Rev. 2013).

  1. Memory T cells with stem cell-like properties in health and disease
    The ability to remember and respond more robustly in a second encounter with a pathogen is a critical property of the adaptive immune system. This process has been proposed to involve a stem cell-like memory T-cell subset (TSCM), able to rapidly differentiate in effectors and self-renew upon antigen re-encounter. We identified conditions to genetically modify and expand long-living TSCM with the ability to self renew and the plasticity to differentiate into potent effectors. (Cieri et al., Blood 2013).
  2. Suicide gene therapy in allogeneic stem cell transplantation
    The transfer of a suicide gene into donor lymphocytes promotes rapid and effective immune reconstitution and control of GvHD. Building on clinical results of suicide gene therapy trials, we are currently designing innovative approaches of T cell manipulation designed to potentiate the graftversus- leukemia effect of donor lymphocytes (Casucci et al., Mol. Ther. 2013).
  3.  TCR gene editing
    To completely and permanently substitute T cell specificity, we developed the TCR gene editing approach based on: i. Somatic knockout of the endogenous TCR genes (by transient exposure to α and/or β chain specific Zinc Finger Nucleases- ZFN), and ii. Introduction of a tumor-specific TCR by lentiviral vectors. This approach, was validated in vitro and in vivo with different TCRs specific for antigens expressed by acute leukemias and multiple myelomas (Provasi, Genovese, et al., Nat. Med 2012).

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