Document 0775
 DOCN  M94B0775
 TI    Genetically modified T-cell clones as a treatment for human viral
       diseases (Meeting abstract).
 DT    9412
 AU    Riddell SR; Overell RW; Lupton S; Greenberg PD; Fred Hutchinson Cancer
       Res. Center, 1124 Columbia St., Seattle,; WA 98104
 SO    SBT93: Society for Biological Therapy, 8th Annual Scientific Meeting:
       Biological Therapy of Cancer--VIII. November 10-14, 1993, Nashville, TN,
       p. 50, 1993.. Unique Identifier : AIDSLINE ICDB/94699586
 AB    The adoptive transfer of MHC restricted antigen-specific T cells is an
       effective therapy for viral diseases and malignancies in animal models.
       Recent advances in the in vitro isolation and expansion of human
       antigen-specific T cell clones have facilitated the development of
       clinical trials to define the principles for successful T cell transfer
       and to evaluate the safety and efficacy of selectively reconstituting or
       augmenting T cell immunity in humans. A phase I study involving 12
       immunodeficient bone marrow transplant recipients has evaluated the
       adoptive transfer to the transplant recipient of CD8+ class 1 MHC
       restricted CMV-specific T cell clones isolated from the respective
       immunocompetent allogeneic bone marrow donor. This study has
       demonstrated that the infusion of greater than 3 x 10(9) clonally
       derived T cells is safe and effective for reconstituting protective CD8+
       CMV-specific CTL responses in the recipient. Using PCR analysis of the
       unique T cell receptor gene rearrangements expressed by transferred CTL,
       we have shown that the transferred CMV-specific T cell clones can
       persist in vivo for at least 12 weeks after infusion. Studies in HIV
       seropositive individuals to evaluate adoptive transfer as an approach
       for augmenting CD8+ CTL responses to conserved epitopes of HIV proteins
       have been initiated. There are unique considerations in applying this
       therapy to HIV infection. Firstly, because of the nature of the host
       cells infected with HIV, which may include microglial cells in the CNS
       and alveolar macrophages in the lungs, there exists the potential for
       toxicity if an exuberant inflammatory response is induced by transferred
       CTL migrating to these sites. Secondly, the in vivo survival of
       transferred CTL may be uniquely compromised by the progressive
       immunodeficiency induced by HIV. Thus, in this study the CD8+
       HIV-specific T cell clones to be used in therapy are modified by
       retrovirus-medicated gene transfer to express a fusion gene consisting
       of the hygromycin phosphotransferase gene and the herpes virus thymidine
       kinase gene (HyTK). Transduced T cell clones can be selected in
       hygromycin and propagated to large numbers with retention of functional
       properties. The HyTK gene serves as a marker to monitor in vivo
       persistence of adoptively transferred CTL and since transduced cells are
       susceptible to ablation by exposure to ganciclovir in vitro, may provide
       a means of ablating the cells in vivo if toxicity occurs. This strategy
       of having an inducible suicide gene in T cells used for immunotherapy
       will provide a safety measure for investigations of T cell clones that
       have been genetically modified to alter functional properties, such as
       cytokine production or migration patterns, that may improve the
       feasibility and efficacy of T cell transfer.
 DE    Clone Cells  HIV Seropositivity/IMMUNOLOGY/THERAPY
       Herpesviridae/ENZYMOLOGY/IMMUNOLOGY  Human  *Immunotherapy, Adoptive
       Phosphotransferases (Alcohol Group Acceptor)/GENETICS
       *T-Lymphocytes/IMMUNOLOGY  T-Lymphocytes,
       Cytotoxic/IMMUNOLOGY/TRANSPLANTATION  T-Lymphocytes,
       Suppressor-Effector/IMMUNOLOGY  Thymidine Kinase/GENETICS  Transduction,
       Genetic  Virus Diseases/IMMUNOLOGY/*THERAPY  MEETING ABSTRACT

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).