Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
Genetically modified T-cell clones as a treatment for human viral diseases (Meeting abstract).
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 Riddell SR; Overell RW; Lupton S; Greenberg PD; Fred Hutchinson Cancer Res. Center, 1124 Columbia St., Seattle,; WA 98104
Abstract:
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.
Keywords: Clone Cells Herpesviridae/ENZYMOLOGY/IMMUNOLOGY Human HIV Seropositivity/IMMUNOLOGY/THERAPY *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 ABSTRACT 941230
M94C4334
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Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
